Structural basis for a novel intrapeptidyl H‐bond and reverse binding of c‐Cbl‐TKB domain substrates
Abstract The c‐Cbl tyrosine kinase binding domain (Cbl‐TKB), essentially an ‘embedded’ SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate‐bindin...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Ng, Cherlyn [verfasserIn] Jackson, Rebecca A [verfasserIn] Buschdorf, Jan P [verfasserIn] Sun, Qingxiang [verfasserIn] Guy, Graeme R [verfasserIn] Sivaraman, J [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2008 |
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| Schlagwörter: |
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| Anmerkung: |
© European Molecular Biology Organization 2008 |
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| Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 27(2008), 5 vom: 14. Feb., Seite 804-816 |
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| Übergeordnetes Werk: |
volume:27 ; year:2008 ; number:5 ; day:14 ; month:02 ; pages:804-816 |
| Links: |
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| DOI / URN: |
10.1038/emboj.2008.18 |
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| Katalog-ID: |
SPR057860351 |
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| 024 | 7 | |a 10.1038/emboj.2008.18 |2 doi | |
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| 041 | |a eng | ||
| 100 | 1 | |a Ng, Cherlyn |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Structural basis for a novel intrapeptidyl H‐bond and reverse binding of c‐Cbl‐TKB domain substrates |
| 264 | 1 | |c 2008 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a © European Molecular Biology Organization 2008 | ||
| 520 | |a Abstract The c‐Cbl tyrosine kinase binding domain (Cbl‐TKB), essentially an ‘embedded’ SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate‐binding affinity, we compared crystal structures of the Cbl‐TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c‐Met receptors and validated the binding with point‐mutational analyses using full‐length proteins. An obligatory, intrapeptidyl H‐bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orientates the peptide into a positively charged pocket on c‐Cbl. Surprisingly, c‐Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H‐bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c‐Cbl; this may enable the selective sequestration of c‐Cbl from other target proteins. | ||
| 650 | 4 | |a c‐Cbl |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a EGFR |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Met |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a reverse binding |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Sprouty |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a TKB domain |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a X‐ray crystallography |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Jackson, Rebecca A |e verfasserin |4 aut | |
| 700 | 1 | |a Buschdorf, Jan P |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Qingxiang |e verfasserin |4 aut | |
| 700 | 1 | |a Guy, Graeme R |e verfasserin |4 aut | |
| 700 | 1 | |a Sivaraman, J |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The EMBO Journal |d Nature Publishing Group UK, 2023 |g 27(2008), 5 vom: 14. Feb., Seite 804-816 |w (DE-627)266022529 |w (DE-600)1467419-1 |x 1460-2075 |7 nnns |
| 773 | 1 | 8 | |g volume:27 |g year:2008 |g number:5 |g day:14 |g month:02 |g pages:804-816 |
| 856 | 4 | 0 | |u https://dx.doi.org/10.1038/emboj.2008.18 |m X:SPRINGER |x Resolving-System |z lizenzpflichtig |3 Volltext |
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| 912 | |a GBV_ILN_62 | ||
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| 912 | |a GBV_ILN_187 | ||
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| 912 | |a GBV_ILN_2005 | ||
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| 912 | |a GBV_ILN_2008 | ||
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| 912 | |a GBV_ILN_2027 | ||
| 912 | |a GBV_ILN_2034 | ||
| 912 | |a GBV_ILN_2037 | ||
| 912 | |a GBV_ILN_2038 | ||
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| 912 | |a GBV_ILN_2048 | ||
| 912 | |a GBV_ILN_2049 | ||
| 912 | |a GBV_ILN_2050 | ||
| 912 | |a GBV_ILN_2055 | ||
| 912 | |a GBV_ILN_2056 | ||
| 912 | |a GBV_ILN_2057 | ||
| 912 | |a GBV_ILN_2059 | ||
| 912 | |a GBV_ILN_2061 | ||
| 912 | |a GBV_ILN_2064 | ||
| 912 | |a GBV_ILN_2068 | ||
| 912 | |a GBV_ILN_2088 | ||
| 912 | |a GBV_ILN_2093 | ||
| 912 | |a GBV_ILN_2106 | ||
| 912 | |a GBV_ILN_2108 | ||
| 912 | |a GBV_ILN_2110 | ||
| 912 | |a GBV_ILN_2111 | ||
| 912 | |a GBV_ILN_2113 | ||
| 912 | |a GBV_ILN_2118 | ||
| 912 | |a GBV_ILN_2119 | ||
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| 912 | |a GBV_ILN_2147 | ||
| 912 | |a GBV_ILN_2148 | ||
| 912 | |a GBV_ILN_2152 | ||
| 912 | |a GBV_ILN_2153 | ||
| 912 | |a GBV_ILN_2188 | ||
| 912 | |a GBV_ILN_2190 | ||
| 912 | |a GBV_ILN_2232 | ||
| 912 | |a GBV_ILN_2336 | ||
| 912 | |a GBV_ILN_2470 | ||
| 912 | |a GBV_ILN_2472 | ||
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| 912 | |a GBV_ILN_2522 | ||
| 912 | |a GBV_ILN_2548 | ||
| 912 | |a GBV_ILN_4012 | ||
| 912 | |a GBV_ILN_4029 | ||
| 912 | |a GBV_ILN_4035 | ||
| 912 | |a GBV_ILN_4037 | ||
| 912 | |a GBV_ILN_4046 | ||
| 912 | |a GBV_ILN_4112 | ||
| 912 | |a GBV_ILN_4125 | ||
| 912 | |a GBV_ILN_4126 | ||
| 912 | |a GBV_ILN_4155 | ||
| 912 | |a GBV_ILN_4242 | ||
| 912 | |a GBV_ILN_4246 | ||
| 912 | |a GBV_ILN_4249 | ||
| 912 | |a GBV_ILN_4251 | ||
| 912 | |a GBV_ILN_4305 | ||
| 912 | |a GBV_ILN_4306 | ||
| 912 | |a GBV_ILN_4307 | ||
| 912 | |a GBV_ILN_4313 | ||
| 912 | |a GBV_ILN_4322 | ||
| 912 | |a GBV_ILN_4323 | ||
| 912 | |a GBV_ILN_4324 | ||
| 912 | |a GBV_ILN_4325 | ||
| 912 | |a GBV_ILN_4326 | ||
| 912 | |a GBV_ILN_4328 | ||
| 912 | |a GBV_ILN_4333 | ||
| 912 | |a GBV_ILN_4334 | ||
| 912 | |a GBV_ILN_4335 | ||
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| 912 | |a GBV_ILN_4338 | ||
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| 912 | |a GBV_ILN_4393 | ||
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| 952 | |d 27 |j 2008 |e 5 |b 14 |c 02 |h 804-816 | ||
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10.1038/emboj.2008.18 doi (DE-627)SPR057860351 (SPR)emboj.2008.18-e DE-627 ger DE-627 rakwb eng Ng, Cherlyn verfasserin aut Structural basis for a novel intrapeptidyl H‐bond and reverse binding of c‐Cbl‐TKB domain substrates 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 2008 Abstract The c‐Cbl tyrosine kinase binding domain (Cbl‐TKB), essentially an ‘embedded’ SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate‐binding affinity, we compared crystal structures of the Cbl‐TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c‐Met receptors and validated the binding with point‐mutational analyses using full‐length proteins. An obligatory, intrapeptidyl H‐bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orientates the peptide into a positively charged pocket on c‐Cbl. Surprisingly, c‐Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H‐bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c‐Cbl; this may enable the selective sequestration of c‐Cbl from other target proteins. c‐Cbl (dpeaa)DE-He213 EGFR (dpeaa)DE-He213 Met (dpeaa)DE-He213 reverse binding (dpeaa)DE-He213 Sprouty (dpeaa)DE-He213 TKB domain (dpeaa)DE-He213 X‐ray crystallography (dpeaa)DE-He213 Jackson, Rebecca A verfasserin aut Buschdorf, Jan P verfasserin aut Sun, Qingxiang verfasserin aut Guy, Graeme R verfasserin aut Sivaraman, J verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 27(2008), 5 vom: 14. Feb., Seite 804-816 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:27 year:2008 number:5 day:14 month:02 pages:804-816 https://dx.doi.org/10.1038/emboj.2008.18 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_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 27 2008 5 14 02 804-816 |
| spelling |
10.1038/emboj.2008.18 doi (DE-627)SPR057860351 (SPR)emboj.2008.18-e DE-627 ger DE-627 rakwb eng Ng, Cherlyn verfasserin aut Structural basis for a novel intrapeptidyl H‐bond and reverse binding of c‐Cbl‐TKB domain substrates 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 2008 Abstract The c‐Cbl tyrosine kinase binding domain (Cbl‐TKB), essentially an ‘embedded’ SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate‐binding affinity, we compared crystal structures of the Cbl‐TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c‐Met receptors and validated the binding with point‐mutational analyses using full‐length proteins. An obligatory, intrapeptidyl H‐bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orientates the peptide into a positively charged pocket on c‐Cbl. Surprisingly, c‐Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H‐bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c‐Cbl; this may enable the selective sequestration of c‐Cbl from other target proteins. c‐Cbl (dpeaa)DE-He213 EGFR (dpeaa)DE-He213 Met (dpeaa)DE-He213 reverse binding (dpeaa)DE-He213 Sprouty (dpeaa)DE-He213 TKB domain (dpeaa)DE-He213 X‐ray crystallography (dpeaa)DE-He213 Jackson, Rebecca A verfasserin aut Buschdorf, Jan P verfasserin aut Sun, Qingxiang verfasserin aut Guy, Graeme R verfasserin aut Sivaraman, J verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 27(2008), 5 vom: 14. Feb., Seite 804-816 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:27 year:2008 number:5 day:14 month:02 pages:804-816 https://dx.doi.org/10.1038/emboj.2008.18 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_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 27 2008 5 14 02 804-816 |
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10.1038/emboj.2008.18 doi (DE-627)SPR057860351 (SPR)emboj.2008.18-e DE-627 ger DE-627 rakwb eng Ng, Cherlyn verfasserin aut Structural basis for a novel intrapeptidyl H‐bond and reverse binding of c‐Cbl‐TKB domain substrates 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 2008 Abstract The c‐Cbl tyrosine kinase binding domain (Cbl‐TKB), essentially an ‘embedded’ SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate‐binding affinity, we compared crystal structures of the Cbl‐TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c‐Met receptors and validated the binding with point‐mutational analyses using full‐length proteins. An obligatory, intrapeptidyl H‐bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orientates the peptide into a positively charged pocket on c‐Cbl. Surprisingly, c‐Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H‐bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c‐Cbl; this may enable the selective sequestration of c‐Cbl from other target proteins. c‐Cbl (dpeaa)DE-He213 EGFR (dpeaa)DE-He213 Met (dpeaa)DE-He213 reverse binding (dpeaa)DE-He213 Sprouty (dpeaa)DE-He213 TKB domain (dpeaa)DE-He213 X‐ray crystallography (dpeaa)DE-He213 Jackson, Rebecca A verfasserin aut Buschdorf, Jan P verfasserin aut Sun, Qingxiang verfasserin aut Guy, Graeme R verfasserin aut Sivaraman, J verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 27(2008), 5 vom: 14. Feb., Seite 804-816 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:27 year:2008 number:5 day:14 month:02 pages:804-816 https://dx.doi.org/10.1038/emboj.2008.18 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_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 27 2008 5 14 02 804-816 |
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10.1038/emboj.2008.18 doi (DE-627)SPR057860351 (SPR)emboj.2008.18-e DE-627 ger DE-627 rakwb eng Ng, Cherlyn verfasserin aut Structural basis for a novel intrapeptidyl H‐bond and reverse binding of c‐Cbl‐TKB domain substrates 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 2008 Abstract The c‐Cbl tyrosine kinase binding domain (Cbl‐TKB), essentially an ‘embedded’ SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate‐binding affinity, we compared crystal structures of the Cbl‐TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c‐Met receptors and validated the binding with point‐mutational analyses using full‐length proteins. An obligatory, intrapeptidyl H‐bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orientates the peptide into a positively charged pocket on c‐Cbl. Surprisingly, c‐Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H‐bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c‐Cbl; this may enable the selective sequestration of c‐Cbl from other target proteins. c‐Cbl (dpeaa)DE-He213 EGFR (dpeaa)DE-He213 Met (dpeaa)DE-He213 reverse binding (dpeaa)DE-He213 Sprouty (dpeaa)DE-He213 TKB domain (dpeaa)DE-He213 X‐ray crystallography (dpeaa)DE-He213 Jackson, Rebecca A verfasserin aut Buschdorf, Jan P verfasserin aut Sun, Qingxiang verfasserin aut Guy, Graeme R verfasserin aut Sivaraman, J verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 27(2008), 5 vom: 14. Feb., Seite 804-816 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:27 year:2008 number:5 day:14 month:02 pages:804-816 https://dx.doi.org/10.1038/emboj.2008.18 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_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 27 2008 5 14 02 804-816 |
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10.1038/emboj.2008.18 doi (DE-627)SPR057860351 (SPR)emboj.2008.18-e DE-627 ger DE-627 rakwb eng Ng, Cherlyn verfasserin aut Structural basis for a novel intrapeptidyl H‐bond and reverse binding of c‐Cbl‐TKB domain substrates 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 2008 Abstract The c‐Cbl tyrosine kinase binding domain (Cbl‐TKB), essentially an ‘embedded’ SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate‐binding affinity, we compared crystal structures of the Cbl‐TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c‐Met receptors and validated the binding with point‐mutational analyses using full‐length proteins. An obligatory, intrapeptidyl H‐bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orientates the peptide into a positively charged pocket on c‐Cbl. Surprisingly, c‐Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H‐bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c‐Cbl; this may enable the selective sequestration of c‐Cbl from other target proteins. c‐Cbl (dpeaa)DE-He213 EGFR (dpeaa)DE-He213 Met (dpeaa)DE-He213 reverse binding (dpeaa)DE-He213 Sprouty (dpeaa)DE-He213 TKB domain (dpeaa)DE-He213 X‐ray crystallography (dpeaa)DE-He213 Jackson, Rebecca A verfasserin aut Buschdorf, Jan P verfasserin aut Sun, Qingxiang verfasserin aut Guy, Graeme R verfasserin aut Sivaraman, J verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 27(2008), 5 vom: 14. Feb., Seite 804-816 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:27 year:2008 number:5 day:14 month:02 pages:804-816 https://dx.doi.org/10.1038/emboj.2008.18 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_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 27 2008 5 14 02 804-816 |
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Enthalten in The EMBO Journal 27(2008), 5 vom: 14. Feb., Seite 804-816 volume:27 year:2008 number:5 day:14 month:02 pages:804-816 |
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Enthalten in The EMBO Journal 27(2008), 5 vom: 14. Feb., Seite 804-816 volume:27 year:2008 number:5 day:14 month:02 pages:804-816 |
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c‐Cbl EGFR Met reverse binding Sprouty TKB domain X‐ray crystallography |
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Ng, Cherlyn @@aut@@ Jackson, Rebecca A @@aut@@ Buschdorf, Jan P @@aut@@ Sun, Qingxiang @@aut@@ Guy, Graeme R @@aut@@ Sivaraman, J @@aut@@ |
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Ng, Cherlyn |
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Ng, Cherlyn misc c‐Cbl misc EGFR misc Met misc reverse binding misc Sprouty misc TKB domain misc X‐ray crystallography Structural basis for a novel intrapeptidyl H‐bond and reverse binding of c‐Cbl‐TKB domain substrates |
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Structural basis for a novel intrapeptidyl H‐bond and reverse binding of c‐Cbl‐TKB domain substrates c‐Cbl (dpeaa)DE-He213 EGFR (dpeaa)DE-He213 Met (dpeaa)DE-He213 reverse binding (dpeaa)DE-He213 Sprouty (dpeaa)DE-He213 TKB domain (dpeaa)DE-He213 X‐ray crystallography (dpeaa)DE-He213 |
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Structural basis for a novel intrapeptidyl H‐bond and reverse binding of c‐Cbl‐TKB domain substrates |
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structural basis for a novel intrapeptidyl h‐bond and reverse binding of c‐cbl‐tkb domain substrates |
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Structural basis for a novel intrapeptidyl H‐bond and reverse binding of c‐Cbl‐TKB domain substrates |
| abstract |
Abstract The c‐Cbl tyrosine kinase binding domain (Cbl‐TKB), essentially an ‘embedded’ SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate‐binding affinity, we compared crystal structures of the Cbl‐TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c‐Met receptors and validated the binding with point‐mutational analyses using full‐length proteins. An obligatory, intrapeptidyl H‐bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orientates the peptide into a positively charged pocket on c‐Cbl. Surprisingly, c‐Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H‐bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c‐Cbl; this may enable the selective sequestration of c‐Cbl from other target proteins. © European Molecular Biology Organization 2008 |
| abstractGer |
Abstract The c‐Cbl tyrosine kinase binding domain (Cbl‐TKB), essentially an ‘embedded’ SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate‐binding affinity, we compared crystal structures of the Cbl‐TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c‐Met receptors and validated the binding with point‐mutational analyses using full‐length proteins. An obligatory, intrapeptidyl H‐bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orientates the peptide into a positively charged pocket on c‐Cbl. Surprisingly, c‐Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H‐bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c‐Cbl; this may enable the selective sequestration of c‐Cbl from other target proteins. © European Molecular Biology Organization 2008 |
| abstract_unstemmed |
Abstract The c‐Cbl tyrosine kinase binding domain (Cbl‐TKB), essentially an ‘embedded’ SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate‐binding affinity, we compared crystal structures of the Cbl‐TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c‐Met receptors and validated the binding with point‐mutational analyses using full‐length proteins. An obligatory, intrapeptidyl H‐bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orientates the peptide into a positively charged pocket on c‐Cbl. Surprisingly, c‐Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H‐bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c‐Cbl; this may enable the selective sequestration of c‐Cbl from other target proteins. © European Molecular Biology Organization 2008 |
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Structural basis for a novel intrapeptidyl H‐bond and reverse binding of c‐Cbl‐TKB domain substrates |
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https://dx.doi.org/10.1038/emboj.2008.18 |
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Jackson, Rebecca A Buschdorf, Jan P Sun, Qingxiang Guy, Graeme R Sivaraman, J |
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2024-10-18T04:52:32.660Z |
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| score |
7.3992996 |