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Tytuł:
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Interdomain interactions dictate the function of the Candida albicans Hsp110 protein Msi3.
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Autorzy:
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Li H; Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, USA.
Hu L; Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, USA; Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
Cuffee CW; Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, USA.
Mohamed M; Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, USA.
Li Q; Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
Liu Q; Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Tianjin, China.
Zhou L; Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, USA.
Liu Q; Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, USA. Electronic address: .
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Źródło:
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The Journal of biological chemistry [J Biol Chem] 2021 Sep; Vol. 297 (3), pp. 101082. Date of Electronic Publication: 2021 Aug 14.
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Typ publikacji:
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Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
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MeSH Terms:
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HSP110 Heat-Shock Proteins/*chemistry
HSP110 Heat-Shock Proteins/*metabolism
Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Binding Sites/genetics ; Candida albicans/genetics ; Candida albicans/metabolism ; HSP110 Heat-Shock Proteins/genetics ; HSP70 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Molecular Chaperones/metabolism ; Nucleotides/metabolism ; Protein Binding/genetics ; Protein Domains/genetics ; Protein Folding
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Grant Information:
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R01 GM098592 United States GM NIGMS NIH HHS; R01 GM109193 United States GM NIGMS NIH HHS; R21 AI140006 United States AI NIAID NIH HHS
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Contributed Indexing:
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Keywords: ATPase; Hsp110; Hsp70; allosteric regulation; heat shock protein (HSP); molecular chaperone; peptides; protein folding; proteostasis
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Substance Nomenclature:
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0 (HSP110 Heat-Shock Proteins)
0 (HSP70 Heat-Shock Proteins)
0 (Heat-Shock Proteins)
0 (Molecular Chaperones)
0 (Nucleotides)
8L70Q75FXE (Adenosine Triphosphate)
EC 3.6.1.- (Adenosine Triphosphatases)
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Entry Date(s):
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Date Created: 20210817 Date Completed: 20211117 Latest Revision: 20230126
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Update Code:
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20240104
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PubMed Central ID:
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PMC8424595
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DOI:
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10.1016/j.jbc.2021.101082
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PMID:
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34403698
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Heat shock proteins of 110 kDa (Hsp110s), a unique class of molecular chaperones, are essential for maintaining protein homeostasis. Hsp110s exhibit a strong chaperone activity preventing protein aggregation (the "holdase" activity) and also function as the major nucleotide-exchange factor (NEF) for Hsp70 chaperones. Hsp110s contain two functional domains: a nucleotide-binding domain (NBD) and substrate-binding domain (SBD). ATP binding is essential for Hsp110 function and results in close contacts between the NBD and SBD. However, the molecular mechanism of this ATP-induced allosteric coupling remains poorly defined. In this study, we carried out biochemical analysis on Msi3, the sole Hsp110 in Candida albicans, to dissect the unique allosteric coupling of Hsp110s using three mutations affecting the domain-domain interface. All the mutations abolished both the in vivo and in vitro functions of Msi3. While the ATP-bound state was disrupted in all mutants, only mutation of the NBD-SBDβ interfaces showed significant ATPase activity, suggesting that the full-length Hsp110s have an ATPase that is mainly suppressed by NBD-SBDβ contacts. Moreover, the high-affinity ATP-binding unexpectedly appears to require these NBD-SBD contacts. Remarkably, the "holdase" activity was largely intact for all mutants tested while NEF activity was mostly compromised, although both activities strictly depended on the ATP-bound state, indicating different requirements for these two activities. Stable peptide substrate binding to Msi3 led to dissociation of the NBD-SBD contacts and compromised interactions with Hsp70. Taken together, our data demonstrate that the exceptionally strong NBD-SBD contacts in Hsp110s dictate the unique allosteric coupling and biochemical activities.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Erratum in: J Biol Chem. 2023 Feb;299(2):102879. (PMID: 36669421)
