Jing Li [verfasserIn]

Johannes Buchner [verfasserIn]

E-Artikel

Englisch

2013

Click here to view optimized website for mobile devices Journal is indexed with MEDLINE/Index Medicus and PubMed Share on facebookShare on twitter Share on citeulike Share on googleShare on linkedin More Sharing Services Table of Contents REVIEW ARTICLE Year : 2013 | Volume : 36 | Issue : 3 | Page : 106-117 Structure

Function and Regulation of the Hsp90 Machinery Jing Li1

Johannes Buchner2 1 Division of Biology

California Institute of Technology

Pasadena

California

USA 2 Center for Integrated Protein Science

Department of Chemistry

Technische Universität München

Munich

Germany Date of Submission05-Sep-2012 Date of Acceptance02-Nov-2012 Date of Web Publication10-Jun-2013 Correspondence Address: Johannes Buchner Center for Integrated Protein Science

Technical University of Munich. Lichtenbergstrasse 4

85747 Garching Germany Login to access the Email id Crossref citations19 PMC citations11 DOI: 10.4103/2319-4170.113230 PMID: 23806880 Get Permissions Abstract Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction

intracellular transport

and protein degradation

it became an interesting target for cancer therapy. Structurally

Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function

Hsp90 works together with a large group of cofactors

termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90

which facilitate the maturation of client proteins. In addition

posttranslational modifications of Hsp90

such as phosphorylation and acetylation

provide another level of regulation. They influence the conformational cycle

co-chaperone interaction

and inter-domain communications. In this review

we discuss the recent progress made in understanding the Hsp90 machinery. Keywords: ATPase

clients

co-chaperones

conformational cycle

Hsp90

posttranslational modifications How to cite this article: Li J

Buchner J. Structure

Function and Regulation of the Hsp90 Machinery. Biomed J 2013;36:106-17 How to cite this URL: Li J

Function and Regulation of the Hsp90 Machinery. Biomed J [serial online] 2013 [cited 2014 Dec 31];36:106-17. Available from: http://www.biomedj.org/text.asp?2013/36/3/106/113230 Heat shock protein 90 (Hsp90)

one of the most abundant and conserved molecular chaperones

is essential in eukaryotic cells. [1]

[2] Different from other well-known molecular chaperone like Hsp70 and GroEL/ES

Hsp90 is not required for de novo folding of most proteins but facilitates the final maturation of a selected clientele of proteins. [3] Hsp90 clients include protein kinases

transcription factors such as p53

and steroid hormone receptors (SHRs). [4]

[5]

[6]

[7] Therefore

Hsp90 does not only function in protein folding but also contribute to various cellular processes including signal transduction

and protein degradation. Interestingly

while bacteria possess an Hsp90 protein

called HtpG in Escherichia More Details coli

no Hsp90 gene has been found in archea. [8]

[9]

[10] However

bacterial Hsp90 is not essential and its precise function remains to be investigated. Recent studies suggest that it collaborates with the DnaK (Hsp70) system in substrate remodeling and may function against oxidative stress. [11]

[12] In yeast

there are two Hsp90 isoforms in the cytosol

Hsc82 and Hsp82

of which Hsp82 is up-regulated up to 20 times under heat stress. [2] Hsp90α and Hsp90β are the two major isoforms in the cytoplasm of mammalian cells. Hsp90α is inducible under stress conditions

while Hsp90β is constitutively expressed. [13] Hsp90 analogues also exist in other cellular compartments such as Grp94 in the endoplasmic reticulum

Trap-1 in the mitochondrial matrix

and ch-Hsp90 in the chloroplast. [14]

[15]

[16] Interestingly

Hsp90 can be secreted as well and it promotes tumor invasiveness. Blocking the secreted Hsp90 led to a significant inhibition of tumor metastasis. [17] Structure of Hsp90 Top Structurally

Hsp90 is a homodimer and each protomer contains three flexibly linked regions

an N-terminal ATP-binding domain (N-domain)

a middle domain (M-domain)

and a C-terminal dimerization domain (C-domain) [Figure 1]. [18] Except for the charged linker located between the N- and M-domains in eukaryotic Hsp90

this domain organization is conserved from bacteria to man. Hsp90 is a member of a special class of structurally related

evolutionarily conserved split ATPases

the so-called Gyrase

Histindine Kinase

MutL (GHKL) domain ATPases

which contain a Bergerat ATP-binding fold. [19] Another interesting feature of the ATP binding region is that several conserved amino acid residues form a "lid" that closes over the nucleotide binding pocket in the ATP-bound state but is open during the ADP-bound state. [18] The M-domain of Hsp90 is involved in ATP hydrolysis

as it contains crucial catalytic residues for forming the composite ATPase site. Moreover

the M-domain contributes to the interaction sites for client proteins and some co-chaperones. [20] The C-domain is essential for the dimerization of Hsp90. Interestingly

in eukaryotic Hsp90

the opening of the C-domains is anti-correlated to the closing of the N-domain. [21] A conserved MEEVD motif at the C-terminal end serves as the docking site for the interaction with co-chaperones which contain a tetratricopeptide repeat (TPR) clamp. [22] Figure 1: Open and closed conformation of Hsp90. Crystal structures of full-length Hsp90 from E. coli (HtpG) in the open conformation (left

PDB 2IOQ) and nucleotide-bound yeast Hsp90 in the closed conformation (right

PDB 2CG9). The N-domain is depicted in green

the M-domain in blue

and the C-domain in orange. Click here to view Conformational dynamics of Hsp90 Top Hsp90 is a weak ATPase and the turnover rates are very low

with 1 min–1 for yeast Hsp90 and 0.1 min–1 for human Hsp90. [23]

[24]

[25] Structural studies revealed that Hsp90 spontaneously adopts structurally distinct conformations

which seem to be in a dynamic equilibrium [Figure 1]. [9]

[26] Nucleotide binding induces directionality and a conformational cycle. [9]

[27]

[28] In the apo state

Hsp90 adopts a "V"- shaped form

termed "open conformation" [Figure 1]. ATP binding triggers a series of conformational changes including repositioning of the N-terminal lid region and a dramatic change in the N-M domain orientation. Finally

Hsp90 reaches a more compact state

termed "closed conformation" in which the N-domains are dimerized [Figure 1]. [9]

[18] Recent biophysical studies using ensemble and single molecule fluorescence resonance energy transfer (FRET) assays allowed to further dissect the ATP-induced conformational changes [Figure 2]. [26]

[28] After fast ATP binding

Hsp90 slowly reaches the first intermediate state (I1)

in which the ATP lid is closed but the N-domains are still open. The N-terminal dimerization leads to the formation of the second intermediate state (I2)

in which the M-domain repositions and interacts with the N-domain. Then Hsp90 reaches a fully closed state in which ATP hydrolysis occurs. After ATP is hydrolyzed

the N-domains dissociate

release ADP as well as inorganic phosphate (Pi)

and Hsp90 returns to the open conformation again. [28] Figure 2: Conformational cycle of Hsp90. After fast ATP binding

in which the ATP lid is closed but the N-domains are still open. Then

In: Biomedical Journal - Elsevier, 2013, 36(2013), 3, Seite 106-117

volume:36 ; year:2013 ; number:3 ; pages:106-117

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10.4103/2319-4170.113230

DOAJ079230059