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Article ; Online: Meet the authors: Guy Zoltsman and Rina Rosenzweig.

Zoltsman, Guy / Rosenzweig, Rina

2024 Volume 84, Issue 8, Page(s) 1396–1397

Abstract: We talk to first and last authors Guy Zoltsman and Rina Rosenzweig about their paper, "A unique chaperoning mechanism in Class A JDPs recognizes and stabilizes mutant p53," how every result may be important in the right context, and the importance to ... ...

Abstract	We talk to first and last authors Guy Zoltsman and Rina Rosenzweig about their paper, "A unique chaperoning mechanism in Class A JDPs recognizes and stabilizes mutant p53," how every result may be important in the right context, and the importance to Rina that her lab is an encouraging and collaborative place.
MeSH term(s)	Male ; Humans
Language	English
Publishing date	2024-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2024.03.007
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Article ; Online: Protein disaggregation machineries in the human cytosol.

Wentink, Anne / Rosenzweig, Rina

Current opinion in structural biology

2023 Volume 83, Page(s) 102735

Abstract: Proteins carry out the vast majority of functions in cells, but can only do so when properly folded. Following stress or mutation, proteins can lose their proper fold, resulting in misfolding, inactivity, and aggregation-posing a threat to cellular ... ...

Abstract	Proteins carry out the vast majority of functions in cells, but can only do so when properly folded. Following stress or mutation, proteins can lose their proper fold, resulting in misfolding, inactivity, and aggregation-posing a threat to cellular health. In order to counteract protein aggregation, cells have evolved a remarkable subset of molecular chaperones, called protein disaggregases, which collaboratively possess the ability to forcibly untangle protein aggregates. Here, we review the different chaperone disaggregation machineries present in the human cytosol and their mechanisms of action. Understanding, how these disaggregases function, is both universally and clinically important, as protein aggregation has been linked to multiple, debilitating neurodegenerative diseases.
MeSH term(s)	Humans ; HSP70 Heat-Shock Proteins/metabolism ; Cytosol/metabolism ; Protein Aggregates ; Molecular Chaperones/metabolism ; Protein Folding
Chemical Substances	HSP70 Heat-Shock Proteins ; Protein Aggregates ; Molecular Chaperones
Language	English
Publishing date	2023-11-23
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2023.102735
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Article ; Online: Hsp104 N-terminal domain interaction with substrates plays a regulatory role in protein disaggregation.

Harari, Anna / Zoltsman, Guy / Levin, Tal / Rosenzweig, Rina

The FEBS journal

2022 Volume 289, Issue 17, Page(s) 5359–5377

Abstract: Heat shock protein 104 (Hsp104) protein disaggregases are powerful molecular machines that harness the energy derived from ATP binding and hydrolysis to disaggregate a wide range of protein aggregates and amyloids, as well as to assist in yeast prion ... ...

Abstract	Heat shock protein 104 (Hsp104) protein disaggregases are powerful molecular machines that harness the energy derived from ATP binding and hydrolysis to disaggregate a wide range of protein aggregates and amyloids, as well as to assist in yeast prion propagation. Little is known, however, about how Hsp104 chaperones recognize such a diversity of substrates, or indeed the contribution of the substrate-binding N-terminal domain (NTD) to Hsp104 function. Herein, we present a NMR spectroscopy study, which structurally characterizes the Hsp104 NTD-substrate interaction. We show that the NTD includes a substrate-binding groove that specifically recognizes exposed hydrophobic stretches in unfolded, misfolded, amyloid and prion substrates of Hsp104. In addition, we find that the NTD itself has chaperoning activities which help to protect the exposed hydrophobic regions of its substrates from further misfolding and aggregation, thereby priming them for threading through the Hsp104 central channel. We further demonstrate that mutations to this substrate-binding groove abolish Hsp104 activation by client proteins and keep the chaperone in a partially inhibited state. The Hsp104 variant with these mutations also exhibited significantly reduced disaggregation activity and cell survival at extreme temperatures. Together, our findings provide both a detailed characterization of the NTD-substrate complex and insight into the functional regulatory role of the NTD in protein disaggregation and yeast thermotolerance.
MeSH term(s)	HSP70 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins/metabolism ; Molecular Chaperones/metabolism ; Prions/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism
Chemical Substances	HSP70 Heat-Shock Proteins ; Heat-Shock Proteins ; Molecular Chaperones ; Prions ; Saccharomyces cerevisiae Proteins ; HsP104 protein, S cerevisiae (143012-44-6)
Language	English
Publishing date	2022-03-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16441
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Article: Hsp104 N‐terminal domain interaction with substrates plays a regulatory role in protein disaggregation

Harari, Anna / Zoltsman, Guy / Levin, Tal / Rosenzweig, Rina

FEBS journal. 2022 Sept., v. 289, no. 17

2022

Abstract	Heat shock protein 104 (Hsp104) protein disaggregases are powerful molecular machines that harness the energy derived from ATP binding and hydrolysis to disaggregate a wide range of protein aggregates and amyloids, as well as to assist in yeast prion propagation. Little is known, however, about how Hsp104 chaperones recognize such a diversity of substrates, or indeed the contribution of the substrate‐binding N‐terminal domain (NTD) to Hsp104 function. Herein, we present a NMR spectroscopy study, which structurally characterizes the Hsp104 NTD‐substrate interaction. We show that the NTD includes a substrate‐binding groove that specifically recognizes exposed hydrophobic stretches in unfolded, misfolded, amyloid and prion substrates of Hsp104. In addition, we find that the NTD itself has chaperoning activities which help to protect the exposed hydrophobic regions of its substrates from further misfolding and aggregation, thereby priming them for threading through the Hsp104 central channel. We further demonstrate that mutations to this substrate‐binding groove abolish Hsp104 activation by client proteins and keep the chaperone in a partially inhibited state. The Hsp104 variant with these mutations also exhibited significantly reduced disaggregation activity and cell survival at extreme temperatures. Together, our findings provide both a detailed characterization of the NTD‐substrate complex and insight into the functional regulatory role of the NTD in protein disaggregation and yeast thermotolerance.
Keywords	amyloid ; cell viability ; energy ; heat shock proteins ; heat tolerance ; hydrolysis ; hydrophobicity ; nuclear magnetic resonance spectroscopy ; prions ; yeasts
Language	English
Dates of publication	2022-09
Size	p. 5359-5377.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16441
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Article: Structural and Biochemical Properties of Hsp40/Hsp70 Chaperone System.

Faust, Ofrah / Rosenzweig, Rina

Advances in experimental medicine and biology

2020 Volume 1243, Page(s) 3–20

Abstract: Hsp70s are ubiquitous molecular chaperones that act in a myriad of cellular functions, affecting virtually all aspects in the life of proteins from synthesis to degradation. Hsp70 proteins act in the cell in cooperation with a large set of dedicated co- ... ...

Abstract	Hsp70s are ubiquitous molecular chaperones that act in a myriad of cellular functions, affecting virtually all aspects in the life of proteins from synthesis to degradation. Hsp70 proteins act in the cell in cooperation with a large set of dedicated co-chaperones consisting of J-domain proteins and nucleotide exchange factors that regulate the Hsp70 chaperone cycle. Recent studies have made significant progress towards obtaining a better understanding of the mechanisms through which Hsp70s and their co-chaperones operate, providing insights into structural, kinetic, and functional features of the various members of this network. In this chapter we describe the emerging working principles of the Hsp70 machine and its co-chaperones, and highlight how mechanistic aspects of this network are tied to distinct protein folding functions.
MeSH term(s)	Animals ; HSP40 Heat-Shock Proteins/chemistry ; HSP40 Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/chemistry ; HSP70 Heat-Shock Proteins/metabolism ; Humans ; Kinetics ; Protein Folding
Chemical Substances	HSP40 Heat-Shock Proteins ; HSP70 Heat-Shock Proteins
Language	English
Publishing date	2020-04-15
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-40204-4_1
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Article ; Online: DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones.

Abayev-Avraham, Meital / Salzberg, Yehuda / Gliksberg, Dar / Oren-Suissa, Meital / Rosenzweig, Rina

Nature communications

2023 Volume 14, Issue 1, Page(s) 7066

Abstract: Molecular chaperones are essential cellular components that aid in protein folding and preventing the abnormal aggregation of disease-associated proteins. Mutations in one such chaperone, DNAJB6, were identified in patients with LGMDD1, a dominant ... ...

Abstract	Molecular chaperones are essential cellular components that aid in protein folding and preventing the abnormal aggregation of disease-associated proteins. Mutations in one such chaperone, DNAJB6, were identified in patients with LGMDD1, a dominant autosomal disorder characterized by myofibrillar degeneration and accumulations of aggregated protein within myocytes. The molecular mechanisms through which such mutations cause this dysfunction, however, are not well understood. Here we employ a combination of solution NMR and biochemical assays to investigate the structural and functional changes in LGMDD1 mutants of DNAJB6. Surprisingly, we find that DNAJB6 disease mutants show no reduction in their aggregation-prevention activity in vitro, and instead differ structurally from the WT protein, affecting their interaction with Hsp70 chaperones. While WT DNAJB6 contains a helical element regulating its ability to bind and activate Hsp70, in LGMDD1 disease mutants this regulation is disrupted. These variants can thus recruit and hyperactivate Hsp70 chaperones in an unregulated manner, depleting Hsp70 levels in myocytes, and resulting in the disruption of proteostasis. Interfering with DNAJB6-Hsp70 binding, however, reverses the disease phenotype, suggesting future therapeutic avenues for LGMDD1.
MeSH term(s)	Humans ; Gain of Function Mutation ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; HSP40 Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/genetics ; HSP70 Heat-Shock Proteins/metabolism ; Protein Folding ; Nerve Tissue Proteins/genetics
Chemical Substances	Molecular Chaperones ; HSP40 Heat-Shock Proteins ; HSP70 Heat-Shock Proteins ; DNAJB6 protein, human ; Nerve Tissue Proteins
Language	English
Publishing date	2023-11-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-42735-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Cross-Polarization Schemes for Improved Heteronuclear Transfers Involving Labile Protons in Biomolecular Solution NMR.

Kim, Jihyun / Grün, J Tassilo / Novakovic, Mihajlo / Kupce, Eriks / Rosenzweig, Rina / Frydman, Lucio

Angewandte Chemie (International ed. in English)

2023 Volume 62, Issue 35, Page(s) e202304900

Abstract: INEPT-based experiments are widely used ... ...

Abstract	INEPT-based experiments are widely used for
Language	English
Publishing date	2023-07-18
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202304900
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Article ; Online: A unique chaperoning mechanism in class A JDPs recognizes and stabilizes mutant p53.

Zoltsman, Guy / Dang, Thi Lieu / Kuchersky, Miriam / Faust, Ofrah / Silva, Micael S / Ilani, Tal / Wentink, Anne S / Bukau, Bernd / Rosenzweig, Rina

Molecular cell

2024 Volume 84, Issue 8, Page(s) 1512–1526.e9

Abstract: J-domain proteins (JDPs) constitute a large family of molecular chaperones that bind a broad spectrum of substrates, targeting them to Hsp70, thus determining the specificity of and activating the entire chaperone functional cycle. The malfunction of ... ...

Abstract	J-domain proteins (JDPs) constitute a large family of molecular chaperones that bind a broad spectrum of substrates, targeting them to Hsp70, thus determining the specificity of and activating the entire chaperone functional cycle. The malfunction of JDPs is therefore inextricably linked to myriad human disorders. Here, we uncover a unique mechanism by which chaperones recognize misfolded clients, present in human class A JDPs. Through a newly identified β-hairpin site, these chaperones detect changes in protein dynamics at the initial stages of misfolding, prior to exposure of hydrophobic regions or large structural rearrangements. The JDPs then sequester misfolding-prone proteins into large oligomeric assemblies, protecting them from aggregation. Through this mechanism, class A JDPs bind destabilized p53 mutants, preventing clearance of these oncoproteins by Hsp70-mediated degradation, thus promoting cancer progression. Removal of the β-hairpin abrogates this protective activity while minimally affecting other chaperoning functions. This suggests the class A JDP β-hairpin as a highly specific target for cancer therapeutics.
MeSH term(s)	Humans ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Neoplasms ; Protein Folding
Chemical Substances	Tumor Suppressor Protein p53 ; Molecular Chaperones ; HSP70 Heat-Shock Proteins
Language	English
Publishing date	2024-03-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2024.02.018
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Article ; Online: Solution NMR Spectroscopy Provides an Avenue for the Study of Functionally Dynamic Molecular Machines: The Example of Protein Disaggregation.

Rosenzweig, Rina / Kay, Lewis E

Journal of the American Chemical Society

2016 Volume 138, Issue 5, Page(s) 1466–1477

Abstract: Solution-based NMR spectroscopy has been an important tool for studying the structure and dynamics of relatively small proteins and protein complexes with aggregate molecular masses under approximately 50 kDa. The development of new experiments and ... ...

Abstract	Solution-based NMR spectroscopy has been an important tool for studying the structure and dynamics of relatively small proteins and protein complexes with aggregate molecular masses under approximately 50 kDa. The development of new experiments and labeling schemes, coupled with continued improvements in hardware, has significantly reduced this size limitation, enabling atomic-resolution studies of molecular machines in the 1 MDa range. In this Perspective, some of the important advances are highlighted in the context of studies of molecular chaperones involved in protein disaggregation. New insights into the structural biology of disaggregation obtained from NMR studies are described, focusing on the unique capabilities of the methodology for obtaining atomic-resolution descriptions of dynamic systems.
MeSH term(s)	Nuclear Magnetic Resonance, Biomolecular/methods ; Protein Structure, Secondary ; Proteins/chemistry ; Substrate Specificity
Chemical Substances	Proteins
Language	English
Publishing date	2016-02-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.5b11346
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Article ; Online: Hsp40s play complementary roles in the prevention of tau amyloid formation.

Irwin, Rose / Faust, Ofrah / Petrovic, Ivana / Wolf, Sharon Grayer / Hofmann, Hagen / Rosenzweig, Rina

eLife

2021 Volume 10

Abstract: The microtubule-associated protein, tau, is the major subunit of neurofibrillary tangles associated with neurodegenerative conditions, such as Alzheimer's disease. In the cell, however, tau aggregation can be prevented by a class of proteins known as ... ...

Abstract	The microtubule-associated protein, tau, is the major subunit of neurofibrillary tangles associated with neurodegenerative conditions, such as Alzheimer's disease. In the cell, however, tau aggregation can be prevented by a class of proteins known as molecular chaperones. While numerous chaperones are known to interact with tau, though, little is known regarding the mechanisms by which these prevent tau aggregation. Here, we describe the effects of ATP-independent Hsp40 chaperones, DNAJA2 and DNAJB1, on tau amyloid-fiber formation and compare these to the small heat shock protein HSPB1. We find that the chaperones play complementary roles, with each preventing tau aggregation differently and interacting with distinct sets of tau species. Whereas HSPB1 only binds tau monomers, DNAJB1 and DNAJA2 recognize aggregation-prone conformers and even mature fibers. In addition, we find that both Hsp40s bind tau seeds and fibers via their C-terminal domain II (CTDII), with DNAJA2 being further capable of recognizing tau monomers by a second, distinct site in CTDI. These results lay out the mechanisms by which the diverse members of the Hsp40 family counteract the formation and propagation of toxic tau aggregates and highlight the fact that chaperones from different families/classes play distinct, yet complementary roles in preventing pathological protein aggregation.
MeSH term(s)	Amyloidogenic Proteins ; Escherichia coli ; HSP40 Heat-Shock Proteins/genetics ; HSP40 Heat-Shock Proteins/metabolism ; Mutation ; Protein Aggregation, Pathological ; tau Proteins/chemistry ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	Amyloidogenic Proteins ; HSP40 Heat-Shock Proteins ; tau Proteins
Language	English
Publishing date	2021-08-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.69601
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