title: Proposal for a role of the Hsp90/Hsp70-based chaperone machinery in making triage decisions when proteins undergo oxidative and toxic damage.
abstract: The Hsp90/Hsp70-based chaperone machinery plays a well-established role in signaling protein function, trafficking and turnover. A number of recent observations also support the notion that Hsp90 and Hsp70 play key roles in the triage of damaged and aberrant proteins for degradation via the ubiquitin-proteasome pathway. In the mid-1990s, it was discovered that Hsp70 is required for ubiquitin-dependent degradation of short-lived and abnormal proteins, and it became clear that inhibition of Hsp90 uniformly leads to the proteasomal degradation of Hsp90 client proteins. Subsequently, CHIP and parkin were shown to be Hsp70-binding ubiquitin E3 ligases that direct ubiquitin-charged E2 enzymes to the Hsp70-bound client protein. Stabilization by Hsp90 reflects the interaction of the chaperone with the ligand binding cleft of the client protein. These hydrophobic clefts must be open to allow passage of ligands to binding sites in the protein interior, and they are inherent sites of conformational instability. Hsp90 stabilizes the open state of the cleft and prevents Hsp70-dependent ubiquitination. In the model we propose here, progressive oxidative events result in cleft opening as the initial step in protein unfolding, and as long as Hsp90 can interact to stabilize the cleft, it will buffer the effect of oxidative damage. When cleft opening is such that Hsp90 can no longer interact, Hsp70-dependent ubiquitination occurs. We summarize evidence that Hsp90 interacts very dynamically with a variety of proteins that are not classic Hsp90 clients, and we show that this dynamic cycling of Hsp90 with nitric oxide synthase protects against CHIP-mediated ubiquitination. Scientific interest to date has focused on stringent regulation of the classic client proteins, which have metastable clefts and are inherently short lived. But, the recognition that Hsp90 cycles dynamically with longer lived proteins with more stable clefts may permit extension of the triage model to the quality control of damaged proteins in general.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, 48109, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Pratt
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Morishima
authors.forename: Hwei-Ming
authors.initials: HM
authors.lastname: Peng
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Osawa
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry; D000818:Animals; D047369:Chromatin Immunoprecipitation; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress; D011485:Protein Binding; D013696:Temperature; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D018832:Molecular Chaperones; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D019001:Nitric Oxide Synthase; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases
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