Identification and function of conformational dynamics in the multidomain GTPase dynamin
Abstract Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen–deuterium exchange coupled with mass spectrometry revealed global nucleotide‐ and membrane‐bindin...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Srinivasan, Saipraveen [verfasserIn] Dharmarajan, Venkatasubramanian [verfasserIn] Reed, Dana Kim [verfasserIn] Griffin, Patrick R [verfasserIn] Schmid, Sandra L [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2016 |
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| Schlagwörter: |
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| Anmerkung: |
© The Authors 2016 |
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| Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 35(2016), 4 vom: 18. Jan., Seite 443-457 |
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| Übergeordnetes Werk: |
volume:35 ; year:2016 ; number:4 ; day:18 ; month:01 ; pages:443-457 |
| Links: |
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| DOI / URN: |
10.15252/embj.201593477 |
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| Katalog-ID: |
SPR057871086 |
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| 100 | 1 | |a Srinivasan, Saipraveen |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Identification and function of conformational dynamics in the multidomain GTPase dynamin |
| 264 | 1 | |c 2016 | |
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| 500 | |a © The Authors 2016 | ||
| 520 | |a Abstract Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen–deuterium exchange coupled with mass spectrometry revealed global nucleotide‐ and membrane‐binding‐dependent conformational changes, as well as the existence of an allosteric relay element in the $ α2^{S} $ helix of the dynamin stalk domain. As predicted from structural studies, FRET analyses detect large movements of the pleckstrin homology domain (PHD) from a ‘closed’ conformation docked near the stalk to an ‘open’ conformation able to interact with membranes. We engineered dynamin constructs locked in either the closed or open state by chemical cross‐linking or deletion mutagenesis and showed that PHD movements function as a conformational switch to regulate dynamin self‐assembly, membrane binding, and fission. This PHD conformational switch is impaired by a centronuclear myopathy‐causing disease mutation, S619L, highlighting the physiological significance of its role in regulating dynamin function. Together, these data provide new insight into coordinated conformational changes that regulate dynamin function and couple membrane binding, oligomerization, and GTPase activity during dynamin‐catalyzed membrane fission. | ||
| 520 | |a Synopsis Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. Ligand‐induced conformational changes in dynamin were identified by HDX‐MS.An allosteric relay helix, $ α2^{S} $, transmits conformational information from the G domain to the membrane and vice versa.FRET analyses reveal conformational switches of the PH domain.When locked in a closed conformation, the PH domain acts in an auto‐inhibitory fashion to regulate membrane binding and assembly.The PH domain conformational switch is impaired in the centronuclear myopathy‐causing mutant Dyn2S619L. | ||
| 520 | |a Graphical Abstract Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. | ||
| 650 | 4 | |a centronuclear myopathy |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a clathrin‐mediated endocytosis |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a hydrogen–deuterium exchange |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a membrane fission |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a pleckstrin homology domain |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Dharmarajan, Venkatasubramanian |e verfasserin |4 aut | |
| 700 | 1 | |a Reed, Dana Kim |e verfasserin |4 aut | |
| 700 | 1 | |a Griffin, Patrick R |e verfasserin |4 aut | |
| 700 | 1 | |a Schmid, Sandra L |e verfasserin |4 aut | |
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10.15252/embj.201593477 doi (DE-627)SPR057871086 (SPR)embj.201593477-e DE-627 ger DE-627 rakwb eng Srinivasan, Saipraveen verfasserin aut Identification and function of conformational dynamics in the multidomain GTPase dynamin 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors 2016 Abstract Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen–deuterium exchange coupled with mass spectrometry revealed global nucleotide‐ and membrane‐binding‐dependent conformational changes, as well as the existence of an allosteric relay element in the $ α2^{S} $ helix of the dynamin stalk domain. As predicted from structural studies, FRET analyses detect large movements of the pleckstrin homology domain (PHD) from a ‘closed’ conformation docked near the stalk to an ‘open’ conformation able to interact with membranes. We engineered dynamin constructs locked in either the closed or open state by chemical cross‐linking or deletion mutagenesis and showed that PHD movements function as a conformational switch to regulate dynamin self‐assembly, membrane binding, and fission. This PHD conformational switch is impaired by a centronuclear myopathy‐causing disease mutation, S619L, highlighting the physiological significance of its role in regulating dynamin function. Together, these data provide new insight into coordinated conformational changes that regulate dynamin function and couple membrane binding, oligomerization, and GTPase activity during dynamin‐catalyzed membrane fission. Synopsis Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. Ligand‐induced conformational changes in dynamin were identified by HDX‐MS.An allosteric relay helix, $ α2^{S} $, transmits conformational information from the G domain to the membrane and vice versa.FRET analyses reveal conformational switches of the PH domain.When locked in a closed conformation, the PH domain acts in an auto‐inhibitory fashion to regulate membrane binding and assembly.The PH domain conformational switch is impaired in the centronuclear myopathy‐causing mutant Dyn2S619L. Graphical Abstract Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. centronuclear myopathy (dpeaa)DE-He213 clathrin‐mediated endocytosis (dpeaa)DE-He213 hydrogen–deuterium exchange (dpeaa)DE-He213 membrane fission (dpeaa)DE-He213 pleckstrin homology domain (dpeaa)DE-He213 Dharmarajan, Venkatasubramanian verfasserin aut Reed, Dana Kim verfasserin aut Griffin, Patrick R verfasserin aut Schmid, Sandra L verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 35(2016), 4 vom: 18. Jan., Seite 443-457 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:35 year:2016 number:4 day:18 month:01 pages:443-457 https://dx.doi.org/10.15252/embj.201593477 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 35 2016 4 18 01 443-457 |
| spelling |
10.15252/embj.201593477 doi (DE-627)SPR057871086 (SPR)embj.201593477-e DE-627 ger DE-627 rakwb eng Srinivasan, Saipraveen verfasserin aut Identification and function of conformational dynamics in the multidomain GTPase dynamin 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors 2016 Abstract Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen–deuterium exchange coupled with mass spectrometry revealed global nucleotide‐ and membrane‐binding‐dependent conformational changes, as well as the existence of an allosteric relay element in the $ α2^{S} $ helix of the dynamin stalk domain. As predicted from structural studies, FRET analyses detect large movements of the pleckstrin homology domain (PHD) from a ‘closed’ conformation docked near the stalk to an ‘open’ conformation able to interact with membranes. We engineered dynamin constructs locked in either the closed or open state by chemical cross‐linking or deletion mutagenesis and showed that PHD movements function as a conformational switch to regulate dynamin self‐assembly, membrane binding, and fission. This PHD conformational switch is impaired by a centronuclear myopathy‐causing disease mutation, S619L, highlighting the physiological significance of its role in regulating dynamin function. Together, these data provide new insight into coordinated conformational changes that regulate dynamin function and couple membrane binding, oligomerization, and GTPase activity during dynamin‐catalyzed membrane fission. Synopsis Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. Ligand‐induced conformational changes in dynamin were identified by HDX‐MS.An allosteric relay helix, $ α2^{S} $, transmits conformational information from the G domain to the membrane and vice versa.FRET analyses reveal conformational switches of the PH domain.When locked in a closed conformation, the PH domain acts in an auto‐inhibitory fashion to regulate membrane binding and assembly.The PH domain conformational switch is impaired in the centronuclear myopathy‐causing mutant Dyn2S619L. Graphical Abstract Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. centronuclear myopathy (dpeaa)DE-He213 clathrin‐mediated endocytosis (dpeaa)DE-He213 hydrogen–deuterium exchange (dpeaa)DE-He213 membrane fission (dpeaa)DE-He213 pleckstrin homology domain (dpeaa)DE-He213 Dharmarajan, Venkatasubramanian verfasserin aut Reed, Dana Kim verfasserin aut Griffin, Patrick R verfasserin aut Schmid, Sandra L verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 35(2016), 4 vom: 18. Jan., Seite 443-457 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:35 year:2016 number:4 day:18 month:01 pages:443-457 https://dx.doi.org/10.15252/embj.201593477 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 35 2016 4 18 01 443-457 |
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10.15252/embj.201593477 doi (DE-627)SPR057871086 (SPR)embj.201593477-e DE-627 ger DE-627 rakwb eng Srinivasan, Saipraveen verfasserin aut Identification and function of conformational dynamics in the multidomain GTPase dynamin 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors 2016 Abstract Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen–deuterium exchange coupled with mass spectrometry revealed global nucleotide‐ and membrane‐binding‐dependent conformational changes, as well as the existence of an allosteric relay element in the $ α2^{S} $ helix of the dynamin stalk domain. As predicted from structural studies, FRET analyses detect large movements of the pleckstrin homology domain (PHD) from a ‘closed’ conformation docked near the stalk to an ‘open’ conformation able to interact with membranes. We engineered dynamin constructs locked in either the closed or open state by chemical cross‐linking or deletion mutagenesis and showed that PHD movements function as a conformational switch to regulate dynamin self‐assembly, membrane binding, and fission. This PHD conformational switch is impaired by a centronuclear myopathy‐causing disease mutation, S619L, highlighting the physiological significance of its role in regulating dynamin function. Together, these data provide new insight into coordinated conformational changes that regulate dynamin function and couple membrane binding, oligomerization, and GTPase activity during dynamin‐catalyzed membrane fission. Synopsis Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. Ligand‐induced conformational changes in dynamin were identified by HDX‐MS.An allosteric relay helix, $ α2^{S} $, transmits conformational information from the G domain to the membrane and vice versa.FRET analyses reveal conformational switches of the PH domain.When locked in a closed conformation, the PH domain acts in an auto‐inhibitory fashion to regulate membrane binding and assembly.The PH domain conformational switch is impaired in the centronuclear myopathy‐causing mutant Dyn2S619L. Graphical Abstract Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. centronuclear myopathy (dpeaa)DE-He213 clathrin‐mediated endocytosis (dpeaa)DE-He213 hydrogen–deuterium exchange (dpeaa)DE-He213 membrane fission (dpeaa)DE-He213 pleckstrin homology domain (dpeaa)DE-He213 Dharmarajan, Venkatasubramanian verfasserin aut Reed, Dana Kim verfasserin aut Griffin, Patrick R verfasserin aut Schmid, Sandra L verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 35(2016), 4 vom: 18. Jan., Seite 443-457 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:35 year:2016 number:4 day:18 month:01 pages:443-457 https://dx.doi.org/10.15252/embj.201593477 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 35 2016 4 18 01 443-457 |
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10.15252/embj.201593477 doi (DE-627)SPR057871086 (SPR)embj.201593477-e DE-627 ger DE-627 rakwb eng Srinivasan, Saipraveen verfasserin aut Identification and function of conformational dynamics in the multidomain GTPase dynamin 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors 2016 Abstract Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen–deuterium exchange coupled with mass spectrometry revealed global nucleotide‐ and membrane‐binding‐dependent conformational changes, as well as the existence of an allosteric relay element in the $ α2^{S} $ helix of the dynamin stalk domain. As predicted from structural studies, FRET analyses detect large movements of the pleckstrin homology domain (PHD) from a ‘closed’ conformation docked near the stalk to an ‘open’ conformation able to interact with membranes. We engineered dynamin constructs locked in either the closed or open state by chemical cross‐linking or deletion mutagenesis and showed that PHD movements function as a conformational switch to regulate dynamin self‐assembly, membrane binding, and fission. This PHD conformational switch is impaired by a centronuclear myopathy‐causing disease mutation, S619L, highlighting the physiological significance of its role in regulating dynamin function. Together, these data provide new insight into coordinated conformational changes that regulate dynamin function and couple membrane binding, oligomerization, and GTPase activity during dynamin‐catalyzed membrane fission. Synopsis Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. Ligand‐induced conformational changes in dynamin were identified by HDX‐MS.An allosteric relay helix, $ α2^{S} $, transmits conformational information from the G domain to the membrane and vice versa.FRET analyses reveal conformational switches of the PH domain.When locked in a closed conformation, the PH domain acts in an auto‐inhibitory fashion to regulate membrane binding and assembly.The PH domain conformational switch is impaired in the centronuclear myopathy‐causing mutant Dyn2S619L. Graphical Abstract Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. centronuclear myopathy (dpeaa)DE-He213 clathrin‐mediated endocytosis (dpeaa)DE-He213 hydrogen–deuterium exchange (dpeaa)DE-He213 membrane fission (dpeaa)DE-He213 pleckstrin homology domain (dpeaa)DE-He213 Dharmarajan, Venkatasubramanian verfasserin aut Reed, Dana Kim verfasserin aut Griffin, Patrick R verfasserin aut Schmid, Sandra L verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 35(2016), 4 vom: 18. Jan., Seite 443-457 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:35 year:2016 number:4 day:18 month:01 pages:443-457 https://dx.doi.org/10.15252/embj.201593477 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 35 2016 4 18 01 443-457 |
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10.15252/embj.201593477 doi (DE-627)SPR057871086 (SPR)embj.201593477-e DE-627 ger DE-627 rakwb eng Srinivasan, Saipraveen verfasserin aut Identification and function of conformational dynamics in the multidomain GTPase dynamin 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors 2016 Abstract Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen–deuterium exchange coupled with mass spectrometry revealed global nucleotide‐ and membrane‐binding‐dependent conformational changes, as well as the existence of an allosteric relay element in the $ α2^{S} $ helix of the dynamin stalk domain. As predicted from structural studies, FRET analyses detect large movements of the pleckstrin homology domain (PHD) from a ‘closed’ conformation docked near the stalk to an ‘open’ conformation able to interact with membranes. We engineered dynamin constructs locked in either the closed or open state by chemical cross‐linking or deletion mutagenesis and showed that PHD movements function as a conformational switch to regulate dynamin self‐assembly, membrane binding, and fission. This PHD conformational switch is impaired by a centronuclear myopathy‐causing disease mutation, S619L, highlighting the physiological significance of its role in regulating dynamin function. Together, these data provide new insight into coordinated conformational changes that regulate dynamin function and couple membrane binding, oligomerization, and GTPase activity during dynamin‐catalyzed membrane fission. Synopsis Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. Ligand‐induced conformational changes in dynamin were identified by HDX‐MS.An allosteric relay helix, $ α2^{S} $, transmits conformational information from the G domain to the membrane and vice versa.FRET analyses reveal conformational switches of the PH domain.When locked in a closed conformation, the PH domain acts in an auto‐inhibitory fashion to regulate membrane binding and assembly.The PH domain conformational switch is impaired in the centronuclear myopathy‐causing mutant Dyn2S619L. Graphical Abstract Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. centronuclear myopathy (dpeaa)DE-He213 clathrin‐mediated endocytosis (dpeaa)DE-He213 hydrogen–deuterium exchange (dpeaa)DE-He213 membrane fission (dpeaa)DE-He213 pleckstrin homology domain (dpeaa)DE-He213 Dharmarajan, Venkatasubramanian verfasserin aut Reed, Dana Kim verfasserin aut Griffin, Patrick R verfasserin aut Schmid, Sandra L verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 35(2016), 4 vom: 18. Jan., Seite 443-457 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:35 year:2016 number:4 day:18 month:01 pages:443-457 https://dx.doi.org/10.15252/embj.201593477 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 35 2016 4 18 01 443-457 |
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English |
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Enthalten in The EMBO Journal 35(2016), 4 vom: 18. Jan., Seite 443-457 volume:35 year:2016 number:4 day:18 month:01 pages:443-457 |
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Enthalten in The EMBO Journal 35(2016), 4 vom: 18. Jan., Seite 443-457 volume:35 year:2016 number:4 day:18 month:01 pages:443-457 |
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centronuclear myopathy clathrin‐mediated endocytosis hydrogen–deuterium exchange membrane fission pleckstrin homology domain |
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The EMBO Journal |
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Srinivasan, Saipraveen @@aut@@ Dharmarajan, Venkatasubramanian @@aut@@ Reed, Dana Kim @@aut@@ Griffin, Patrick R @@aut@@ Schmid, Sandra L @@aut@@ |
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2016-01-18T00:00:00Z |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR057871086</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241018064942.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241018s2016 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/embj.201593477</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR057871086</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)embj.201593477-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Srinivasan, Saipraveen</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Identification and function of conformational dynamics in the multidomain GTPase dynamin</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2016</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Authors 2016</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen–deuterium exchange coupled with mass spectrometry revealed global nucleotide‐ and membrane‐binding‐dependent conformational changes, as well as the existence of an allosteric relay element in the $ α2^{S} $ helix of the dynamin stalk domain. As predicted from structural studies, FRET analyses detect large movements of the pleckstrin homology domain (PHD) from a ‘closed’ conformation docked near the stalk to an ‘open’ conformation able to interact with membranes. We engineered dynamin constructs locked in either the closed or open state by chemical cross‐linking or deletion mutagenesis and showed that PHD movements function as a conformational switch to regulate dynamin self‐assembly, membrane binding, and fission. This PHD conformational switch is impaired by a centronuclear myopathy‐causing disease mutation, S619L, highlighting the physiological significance of its role in regulating dynamin function. Together, these data provide new insight into coordinated conformational changes that regulate dynamin function and couple membrane binding, oligomerization, and GTPase activity during dynamin‐catalyzed membrane fission.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. Ligand‐induced conformational changes in dynamin were identified by HDX‐MS.An allosteric relay helix, $ α2^{S} $, transmits conformational information from the G domain to the membrane and vice versa.FRET analyses reveal conformational switches of the PH domain.When locked in a closed conformation, the PH domain acts in an auto‐inhibitory fashion to regulate membrane binding and assembly.The PH domain conformational switch is impaired in the centronuclear myopathy‐causing mutant Dyn2S619L.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">centronuclear myopathy</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">clathrin‐mediated endocytosis</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">hydrogen–deuterium exchange</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">membrane fission</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">pleckstrin homology domain</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Dharmarajan, Venkatasubramanian</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Reed, Dana Kim</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Griffin, Patrick R</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Schmid, Sandra L</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">The EMBO Journal</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">35(2016), 4 vom: 18. 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|
| author |
Srinivasan, Saipraveen |
| spellingShingle |
Srinivasan, Saipraveen misc centronuclear myopathy misc clathrin‐mediated endocytosis misc hydrogen–deuterium exchange misc membrane fission misc pleckstrin homology domain Identification and function of conformational dynamics in the multidomain GTPase dynamin |
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Identification and function of conformational dynamics in the multidomain GTPase dynamin centronuclear myopathy (dpeaa)DE-He213 clathrin‐mediated endocytosis (dpeaa)DE-He213 hydrogen–deuterium exchange (dpeaa)DE-He213 membrane fission (dpeaa)DE-He213 pleckstrin homology domain (dpeaa)DE-He213 |
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misc centronuclear myopathy misc clathrin‐mediated endocytosis misc hydrogen–deuterium exchange misc membrane fission misc pleckstrin homology domain |
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misc centronuclear myopathy misc clathrin‐mediated endocytosis misc hydrogen–deuterium exchange misc membrane fission misc pleckstrin homology domain |
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misc centronuclear myopathy misc clathrin‐mediated endocytosis misc hydrogen–deuterium exchange misc membrane fission misc pleckstrin homology domain |
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Identification and function of conformational dynamics in the multidomain GTPase dynamin |
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Identification and function of conformational dynamics in the multidomain GTPase dynamin |
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Srinivasan, Saipraveen Dharmarajan, Venkatasubramanian Reed, Dana Kim Griffin, Patrick R Schmid, Sandra L |
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Srinivasan, Saipraveen |
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| title_sort |
identification and function of conformational dynamics in the multidomain gtpase dynamin |
| title_auth |
Identification and function of conformational dynamics in the multidomain GTPase dynamin |
| abstract |
Abstract Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen–deuterium exchange coupled with mass spectrometry revealed global nucleotide‐ and membrane‐binding‐dependent conformational changes, as well as the existence of an allosteric relay element in the $ α2^{S} $ helix of the dynamin stalk domain. As predicted from structural studies, FRET analyses detect large movements of the pleckstrin homology domain (PHD) from a ‘closed’ conformation docked near the stalk to an ‘open’ conformation able to interact with membranes. We engineered dynamin constructs locked in either the closed or open state by chemical cross‐linking or deletion mutagenesis and showed that PHD movements function as a conformational switch to regulate dynamin self‐assembly, membrane binding, and fission. This PHD conformational switch is impaired by a centronuclear myopathy‐causing disease mutation, S619L, highlighting the physiological significance of its role in regulating dynamin function. Together, these data provide new insight into coordinated conformational changes that regulate dynamin function and couple membrane binding, oligomerization, and GTPase activity during dynamin‐catalyzed membrane fission. Synopsis Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. Ligand‐induced conformational changes in dynamin were identified by HDX‐MS.An allosteric relay helix, $ α2^{S} $, transmits conformational information from the G domain to the membrane and vice versa.FRET analyses reveal conformational switches of the PH domain.When locked in a closed conformation, the PH domain acts in an auto‐inhibitory fashion to regulate membrane binding and assembly.The PH domain conformational switch is impaired in the centronuclear myopathy‐causing mutant Dyn2S619L. Graphical Abstract Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. © The Authors 2016 |
| abstractGer |
Abstract Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen–deuterium exchange coupled with mass spectrometry revealed global nucleotide‐ and membrane‐binding‐dependent conformational changes, as well as the existence of an allosteric relay element in the $ α2^{S} $ helix of the dynamin stalk domain. As predicted from structural studies, FRET analyses detect large movements of the pleckstrin homology domain (PHD) from a ‘closed’ conformation docked near the stalk to an ‘open’ conformation able to interact with membranes. We engineered dynamin constructs locked in either the closed or open state by chemical cross‐linking or deletion mutagenesis and showed that PHD movements function as a conformational switch to regulate dynamin self‐assembly, membrane binding, and fission. This PHD conformational switch is impaired by a centronuclear myopathy‐causing disease mutation, S619L, highlighting the physiological significance of its role in regulating dynamin function. Together, these data provide new insight into coordinated conformational changes that regulate dynamin function and couple membrane binding, oligomerization, and GTPase activity during dynamin‐catalyzed membrane fission. Synopsis Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. Ligand‐induced conformational changes in dynamin were identified by HDX‐MS.An allosteric relay helix, $ α2^{S} $, transmits conformational information from the G domain to the membrane and vice versa.FRET analyses reveal conformational switches of the PH domain.When locked in a closed conformation, the PH domain acts in an auto‐inhibitory fashion to regulate membrane binding and assembly.The PH domain conformational switch is impaired in the centronuclear myopathy‐causing mutant Dyn2S619L. Graphical Abstract Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. © The Authors 2016 |
| abstract_unstemmed |
Abstract Vesicle release upon endocytosis requires membrane fission, catalyzed by the large GTPase dynamin. Dynamin contains five domains that together orchestrate its mechanochemical activity. Hydrogen–deuterium exchange coupled with mass spectrometry revealed global nucleotide‐ and membrane‐binding‐dependent conformational changes, as well as the existence of an allosteric relay element in the $ α2^{S} $ helix of the dynamin stalk domain. As predicted from structural studies, FRET analyses detect large movements of the pleckstrin homology domain (PHD) from a ‘closed’ conformation docked near the stalk to an ‘open’ conformation able to interact with membranes. We engineered dynamin constructs locked in either the closed or open state by chemical cross‐linking or deletion mutagenesis and showed that PHD movements function as a conformational switch to regulate dynamin self‐assembly, membrane binding, and fission. This PHD conformational switch is impaired by a centronuclear myopathy‐causing disease mutation, S619L, highlighting the physiological significance of its role in regulating dynamin function. Together, these data provide new insight into coordinated conformational changes that regulate dynamin function and couple membrane binding, oligomerization, and GTPase activity during dynamin‐catalyzed membrane fission. Synopsis Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. Ligand‐induced conformational changes in dynamin were identified by HDX‐MS.An allosteric relay helix, $ α2^{S} $, transmits conformational information from the G domain to the membrane and vice versa.FRET analyses reveal conformational switches of the PH domain.When locked in a closed conformation, the PH domain acts in an auto‐inhibitory fashion to regulate membrane binding and assembly.The PH domain conformational switch is impaired in the centronuclear myopathy‐causing mutant Dyn2S619L. Graphical Abstract Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study. © The Authors 2016 |
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| title_short |
Identification and function of conformational dynamics in the multidomain GTPase dynamin |
| url |
https://dx.doi.org/10.15252/embj.201593477 |
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| author2 |
Dharmarajan, Venkatasubramanian Reed, Dana Kim Griffin, Patrick R Schmid, Sandra L |
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Dharmarajan, Venkatasubramanian Reed, Dana Kim Griffin, Patrick R Schmid, Sandra L |
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10.15252/embj.201593477 |
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2024-10-18T04:52:25.792Z |
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| score |
7.399205 |