The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA repair, development, the immune response and neurodegenerative disease. A large number of co-chaperones interact with HSP90 and regulate the ATPase-associated conformational changes of the HSP90 dimer that occur during the processing of clients. Recent progress has allowed the interactions of clients with HSP90 and its co-chaperones to be defined. Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.

The HSP90 chaperone machinery

Multifaceted roles of disulfide bonds. Peptides as therapeutics.

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

Structure, Function and Regulation of the Hsp90 Machinery

The Hsp90 chaperone machinery: Conformational dynamics and regulation by co-chaperones

Financial support of the Spanish Ministry of Science and
Innovation (CTQ2012-38543-C03) and Generalitat Valenciana
(PROMETEO/2012/020) is acknowledged. V.M.-C. thanks the
Spanish Ministry of Science and Education for a predoctoral
fellowship (FPU AP2007-02562) and Generalitat Valenciana for
a VALi+d postdoctoral fellowship (APOSTD/2013/041).
M.D.P. thanks the Spanish Ministry of Education for a
postdoctoral fellowship and UGC India for a Startup Grant.

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

A general method for constraining peptide conformations via linkage of aromatic sidechains has been developed. Macrocyclization of suitably functionalized tri-, tetra- and pentapeptides via Suzuki–Miyaura cross-coupling has been used to generate side chain to side chain, biaryl-bridged 14- to 21-membered macrocyclic peptides. Biaryl bridges possessing three different configurations, meta–meta, meta–ortho, and ortho–meta, were systematically explored through regiochemical variation of the aryl halide and aryl boronate coupling partners, allowing fine-tuning of the resultant macrocycle conformation. Suzuki–Miyaura macrocyclizations were successfully achieved both in solution and on solid phase for all three sizes of peptide. This approach constitutes a means of constraining peptide conformation via direct carbogenic fusion of side chains of naturally occurring amino acids such as phenylalanine and tyrosine, and so is complementary to strategies involving non-natural, for example, hydrocarbon, bridges.

Biaryl-Bridged Macrocyclic Peptides: Conformational Constraint via Carbogenic Fusion of Natural Amino Acid Side Chains

NF-κB is a major transcription factor that mediates a number of cellular signaling pathways. Crystal structure analysis gives an incomplete picture of the behavior of the protein, particularly in the free state; free monomers or dimers of NF-κB have never been crystallized. NMR analysis gives insights into the structure and dynamics of the protein in solution, but a necessary first step is the assignment of resonances. The size of the heterodimer of the Rel homology regions of the NF-κB monomers p65 and p50 (72 kDa) prohibits the straightforward use of triple-resonance spectroscopy to obtain the assignments. However, the dynamic nature of the free heterodimer, in particular the independence of the DNA-binding and dimerization domains of each monomer, allows the assignments made on differentially labeled smaller domains to be mapped successfully onto the spectrum of the larger full-length RHR. Problematic areas such as the p65 nuclear localization sequence, which is disordered in the free protein, can be approached by residue-specific labeling and comparison with previously-published spectra of a short peptide with the same sequence. Overall, this NMR analysis of NF-κB has given valuable insights into the highly dynamic nature of the free state, which is likely to play an important role in the functional cycle of NF-κB in the cell.

NMR characterization of a 72 kDa transcription factor using differential isotopic labeling.

Hsp90 is a molecular chaperone with a wide array of client proteins, including the tumor suppressor p53. Now the conformation of p53 DNA-binding domain in the presence of full-length or fragments of Hsp90 is studied by HDX and NMR analyses. The results indicate that p53 adopts a looser, molten-globule-like state in the presence of Hsp90.

The client protein p53 adopts a molten globule–like state in the presence of Hsp90

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Biaryl-Bridged Macrocyclic Peptides: Conformational Constraint via Carbogenic Fusion of Natural Amino Acid Side Chains

NMR characterization of a 72 kDa transcription factor using differential isotopic labeling.

The client protein p53 adopts a molten globule–like state in the presence of Hsp90