1. Hsp90: Breaking the Symmetry
Matthias P. Mayer, Laura Le Breton 
Molecular Cell 
Volume 58, Issue 1, Pages 8-20 (April 2015)
DOI: /j.molcel
Copyright © 2015 Elsevier Inc. Terms and Conditions

2. Figure 1 Hsp90 Structure and Conformational Dynamics
From top to bottom, cartoon representations of yeast Hsp90 in closed conformation (PDB ID: 2CG9; Ali et al., 2006), E. coli Hsp90 in ADP bound state (PDB ID: 2IOP; Shiau et al., 2006), canine Grp94 (PDB ID: 2O1U; Dollins et al., 2007), E. coli Hsp90 in nucleotide-free state (PDB ID: 2IOQ; Shiau et al., 2006), E. coli Hsp90 in wide open conformation according to SAXS data (courtesy of D. Agard; Krukenberg et al., 2008). NTD, N-terminal domain (dark blue and dark teal); CL, charged linker (gray, dashed lines represent parts not present in the structure); MD, middle domain (cyan and greencyan); CTD, C-terminal domain (blue and dark green).
Molecular Cell  , 8-20DOI: ( /j.molcel )
Copyright © 2015 Elsevier Inc. Terms and Conditions

3. Figure 2 Hsp90 Chaperone Cycle
In the absence of cochaperones and clients, Hsp90 transits frequently between open and closed conformations through thermal fluctuations (N, N-terminal domain; M, middle domain; C, C-terminal domain). Binding of a single Hop/Sti1 with its TPR2a domain to the C-terminal MEEVD motif and with its TPR2b domain to the MD of one protomer arrests the Hsp90 dimer in a V-shaped open conformation, preventing N-terminal dimerization and ATP hydrolysis. Hsp70 with a bound client (C) interacts with its C-terminal IEEVD motif with the TPR1 domain of Hop leading to the positioning of Hsp70 between the two NTDs of the Hsp90 dimer and to client transfer. Binding of a PPIase (e.g., Cpr6 or FKBP52) to the second MEEVD motif and presumably MD and maybe NTD primes the Hsp90 dimer for Aha1-induced transition to the closed conformation and rapid dissociation of HOP/Sti1 and Hsp70. A second PPIase (e.g., Cpr6, Cpr7, FKBP51, FKBP52, Cyp40) may bind to the free MEEVD motif and other regions of Hsp90. p23/Sba1 displaces Aha1 and stabilizes the Hsp90-client complex with Hsp90 in the closed intertwined conformation. Ligand binding to the client or other forms of client activation may occur in this complex. ATP hydrolysis, maybe in a sequential fashion in both Hsp90 protomers, leads to cochaperone and client dissociation.
Molecular Cell  , 8-20DOI: ( /j.molcel )
Copyright © 2015 Elsevier Inc. Terms and Conditions

4. Figure 3 Asymmetric Structure of TRAP1
Cartoon representation of the crystal structure of Danio rerio TRAP1 (PDB ID: 4IPE; Lavery et al., 2014) with chain B duplicated, in light gray as in the structure and colored (B’-NTD, greencyan; B’-MD, cyan; B’-CTD, deep teal) overlaid to chain A (A-NTD, yellow; A-MD, orange; A-CTD, dark red) to illustrate the asymmetry of the TRAP1 dimer. Arrows indicate how the MD of A is moved out of the symmetric position. For the overlay, NTDs and CTDs were aligned. See Movie S1.
Molecular Cell  , 8-20DOI: ( /j.molcel )
Copyright © 2015 Elsevier Inc. Terms and Conditions

5. Figure 4
Interaction Surfaces and Posttranslational Modifications in Hsp90
(A–C) Surface representations of homology models of human Hsp90α onto the crystal structure of yeast Hsp82 (PDB ID: 2CG9; Ali et al., 2006; left panels) and E. coli HtpG (PDB ID: 2IOQ; Shiau et al., 2006; right panels) (Arnold et al., 2006; Biasini et al., 2014). Protomers colored in light and dark gray with residues involved in cochaperone binding (A), client binding (B), or posttranslationally modified (C) are highlighted as indicated.
(A) We colored residues directly involved in the interaction of Hsp90 with cochaperones as demonstrated by crystallography (Aha1, PDB ID: 1USU, Meyer et al., 2004; Sba1, PDB ID: 2CG9, Ali et al., 2006; Cdc37, PDB ID: 1US7, Roe et al., 2004; Sgt1, PDB ID: 1RL1, Zhang et al., 2008) or implicated in interaction by peak broadening or chemical shift perturbation in NMR experiments (Aha1, Retzlaff et al., 2010; Sti1, Schmid et al., 2012) or protection in hydrogen exchange experiments (Sti1, Lee et al., 2012). Several residues are implicated in binding to more than one cochaperone (colored in purple and dark teal).
(B) We colored residues of Hsp90 implicated in interaction with clients by peak broadening or chemical shift perturbation in NMR experiments, by SAXS-derived models, or by hydrogen exchange data (TAU, courtesy of S. Rüdiger, Karagöz et al., 2014; GR, courtesy of L. Freiburger, Lorenz et al., 2014; p53, Hagn et al., 2011; staphylococcal nuclease Δ131Δ, Street et al., 2012).
(C) We colored residues modified by posttranslational modifications ( Sites only found in a single high-throughput mass spectrometry study are not colored. Lysines only found to be ubiquitinated were also left away for clarity. Right protomer in cartoon representation with sidechains modified posttranslationally as spheres, illustrating the density of posttranslational modifications. Indicated are phosphorylation sites mentioned in the review.
Molecular Cell  , 8-20DOI: ( /j.molcel )
Copyright © 2015 Elsevier Inc. Terms and Conditions

6. Figure 5 Hsp90 Cochaperones
(A) Cochaperones binding simultaneously to Hsp90 during maturation of steroid hormone receptors, kinases, or other Hsp90 clients.
(B) Relative abundance of Hsp90 (Hsp82 and Hsc82) and cochaperones in yeast (Ghaemmaghami et al., 2003).
Molecular Cell  , 8-20DOI: ( /j.molcel )
Copyright © 2015 Elsevier Inc. Terms and Conditions

7. Figure 6
Regulation of the Progression through the Hsp90 Chaperone Cycle by Sequential Phosphorylation
Phosphorylation on Cdc37 regulates its affinity for kinase clients (S13, positive; Y298, negative), and phosphorylation of Hsp90 regulates affinity for Cdc37 (Y197, negative) and Aha1 (Y313, positive; Y627, negative) (Xu et al., 2012). It is unclear whether both protomers of Hsp90 need to be phosphorylated.
Molecular Cell  , 8-20DOI: ( /j.molcel )
Copyright © 2015 Elsevier Inc. Terms and Conditions