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      Review: The HSP90 molecular chaperone—an enigmatic ATPase

      , 1

      Biopolymers

      John Wiley and Sons Inc.

      molecular chaperones, conformational change, ATP, client protein, cochaperone

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          ABSTRACT

          The HSP90 molecular chaperone is involved in the activation and cellular stabilization of a range of ‘client’ proteins, of which oncogenic protein kinases and nuclear steroid hormone receptors are of particular biomedical significance. Work over the last two decades has revealed a conformational cycle critical to the biological function of HSP90, coupled to an inherent ATPase activity that is regulated and manipulated by many of the co‐chaperones proteins with which it collaborates. Pharmacological inhibition of HSP90 ATPase activity results in degradation of client proteins in vivo, and is a promising target for development of new cancer therapeutics. Despite this, the actual function that HSP90s conformationally‐coupled ATPase activity provides in its biological role as a molecular chaperone remains obscure. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 594–607, 2016.

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          Most cited references 89

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          Rapid planetesimal formation in turbulent circumstellar discs

          The initial stages of planet formation in circumstellar gas discs proceed via dust grains that collide and build up larger and larger bodies (Safronov 1969). How this process continues from metre-sized boulders to kilometre-scale planetesimals is a major unsolved problem (Dominik et al. 2007): boulders stick together poorly (Benz 2000), and spiral into the protostar in a few hundred orbits due to a head wind from the slower rotating gas (Weidenschilling 1977). Gravitational collapse of the solid component has been suggested to overcome this barrier (Safronov 1969, Goldreich & Ward 1973, Youdin & Shu 2002). Even low levels of turbulence, however, inhibit sedimentation of solids to a sufficiently dense midplane layer (Weidenschilling & Cuzzi 1993, Dominik et al. 2007), but turbulence must be present to explain observed gas accretion in protostellar discs (Hartmann 1998). Here we report the discovery of efficient gravitational collapse of boulders in locally overdense regions in the midplane. The boulders concentrate initially in transient high pressures in the turbulent gas (Johansen, Klahr, & Henning 2006), and these concentrations are augmented a further order of magnitude by a streaming instability (Youdin & Goodman 2005, Johansen, Henning, & Klahr 2006, Johansen & Youdin 2007) driven by the relative flow of gas and solids. We find that gravitationally bound clusters form with masses comparable to dwarf planets and containing a distribution of boulder sizes. Gravitational collapse happens much faster than radial drift, offering a possible path to planetesimal formation in accreting circumstellar discs.
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            HSP90 at the hub of protein homeostasis: emerging mechanistic insights.

            Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that facilitates the maturation of a wide range of proteins (known as clients). Clients are enriched in signal transducers, including kinases and transcription factors. Therefore, HSP90 regulates diverse cellular functions and exerts marked effects on normal biology, disease and evolutionary processes. Recent structural and functional analyses have provided new insights on the transcriptional and biochemical regulation of HSP90 and the structural dynamics it uses to act on a diverse client repertoire. Comprehensive understanding of how HSP90 functions promises not only to provide new avenues for therapeutic intervention, but to shed light on fundamental biological questions.
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              Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.

              HSP90 is a molecular chaperone that associates with numerous substrate proteins called clients. It plays many important roles in human biology and medicine, but determinants of client recognition by HSP90 have remained frustratingly elusive. We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37. Unexpectedly, many more kinases than transcription factors bound HSP90. CDC37 interacted with kinases, but not with transcription factors or E3 ligases. HSP90::kinase interactions varied continuously over a 100-fold range and provided a platform to study client protein recognition. In wild-type clients, HSP90 did not bind particular sequence motifs, but rather associated with intrinsically unstable kinases. Stabilization of the kinase in either its active or inactive conformation with diverse small molecules decreased HSP90 association. Our results establish HSP90 client recognition as a combinatorial process: CDC37 provides recognition of the kinase family, whereas thermodynamic parameters determine client binding within the family. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Biopolymers
                Biopolymers
                10.1002/(ISSN)1097-0282
                BIP
                Biopolymers
                John Wiley and Sons Inc. (Hoboken )
                0006-3525
                1097-0282
                20 May 2016
                August 2016
                : 105
                : 8 , GTP and ATP Hydrolysis in Biology ( doiID: 10.1002/bip.v105.8 )
                : 594-607
                Affiliations
                [ 1 ] Genome Damage and Stability Centre, School of Life SciencesUniversity of Sussex Falmer Brighton BN1 9QRUK
                Author notes
                [* ] Correspondence to: L. H. Pearl; e‐mail: Laurence.Pearl@ 123456sussex.ac.uk
                Article
                BIP22835
                10.1002/bip.22835
                4879513
                26991466
                © 2016 The Authors. Biopolymers Published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 14
                Product
                Funding
                Funded by: Senior Investigator Award
                Award ID: 095605/Z/11/Z
                Categories
                Article
                Articles
                Custom metadata
                2.0
                bip22835
                August 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:23.06.2016

                Biochemistry

                cochaperone, client protein, atp, conformational change, molecular chaperones

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