Evolution of an intricate J-protein network driving protein disaggregation in eukaryotes

Nillegoda, Nadinath B.; Stank, Antonia; Malinverni, Duccio; Alberts, Niels; Szlachcic, Anna; Barducci, Alessandro; Rios, Paolo De Los; Wade, Rebecca C.; Bukau, Bernd

doi:10.7554/elife.24560

Cited by 65 publications

(96 citation statements)

References 81 publications

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“…How these states contribute to Hsp70 function is currently not clear. Also, as mentioned above class A and class B JDPs form complexes in vitro and in vivo boosting Hsp70 disaggregation activity (89,90,120). Because both class A and class B JDPs are dimers, potentially four J-domains are available for interacting with Hsp70s and could target several Hsp70s simultaneously to bind to aggregates in close proximity to each other.…”

Section: Current Questionsmentioning

confidence: 91%

“…Recently, it was shown that some class A and class B JDPs cooperate in protein disaggregation. This cooperation involves not only a division of labor with DNAJA2 preferentially targeting small aggregates and DNAJB1 large aggregates but even more a direct interaction between the class A and the class B JDP, suggesting the formation of a high order complex with Hsp70s (89,90).…”

Section: J-domain Proteins: Hsp70 Targeting Factorsmentioning

confidence: 99%

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Recent advances in the structural and mechanistic aspects of Hsp70 molecular chaperones

Mayer

Gierasch

2019

Journal of Biological Chemistry

222

239

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Edited by Norma M. Allewell Hsp70 chaperones are central hubs of the protein quality control network and collaborate with co-chaperones having a J-domain (an ϳ70-residue-long helical hairpin with a flexible loop and a conserved His-Pro-Asp motif required for ATP hydrolysis by Hsp70s) and also with nucleotide exchange factors to facilitate many protein-folding processes that (re)establish protein homeostasis. The Hsp70s are highly dynamic nanomachines that modulate the conformation of their substrate polypeptides by transiently binding to short, mostly hydrophobic stretches. This interaction is regulated by an intricate allosteric mechanism. The J-domain co-chaperones target Hsp70 to their polypeptide substrates, and the nucleotide exchange factors regulate the lifetime of the Hsp70 -substrate complexes. Significant advances in recent years are beginning to unravel the molecular mechanism of this chaperone machine and how they treat their substrate proteins. This is the second article in the JBC Reviews series "Molecular chaperones and protein quality control."

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Section: Current Questionsmentioning

confidence: 91%

Section: J-domain Proteins: Hsp70 Targeting Factorsmentioning

confidence: 99%

Recent advances in the structural and mechanistic aspects of Hsp70 molecular chaperones

Mayer

Gierasch

2019

Journal of Biological Chemistry

222

239

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“…The major de novo protein folding chaperones in eukaryotes are Hsp90 and Hsp70. These ATP‐dependent chaperones appear as constitutively expressed and stress‐induced forms and team up with various cochaperones for substrate recognition, binding, and activation . Hsp70 and Hsp90 chaperone systems play a role in different organelles of the eukaryotic cell and regulate a wide range of events including folding of de novo synthesized polypeptides, refolding, or degradation of misfolded proteins.…”

Section: The Chaperone Networkmentioning

confidence: 99%

Repair or destruction—an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis

2017

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Cellular differentiation, developmental processes, and environmental factors challenge the integrity of the proteome in every eukaryotic cell. The maintenance of protein homeostasis, or proteostasis, involves folding and degradation of damaged proteins, and is essential for cellular function, organismal growth, and viability 1, 2. Misfolded proteins that cannot be refolded by chaperone machineries are degraded by specialized proteolytic systems. A major degradation pathway regulating cellular proteostasis is the ubiquitin (Ub)/proteasome system (UPS), which regulates turnover of damaged proteins that accumulate upon stress and during aging. Despite a large number of structurally unrelated substrates, Ub conjugation is remarkably selective. Substrate selectivity is mainly provided by the group of E3 enzymes. Several observations indicate that numerous E3 Ub ligases intimately collaborate with molecular chaperones to maintain the cellular proteome. In this review, we provide an overview of specialized quality control E3 ligases playing a critical role in the degradation of damaged proteins. The process of substrate recognition and turnover, the type of chaperones they team up with, and the potential pathogeneses associated with their malfunction will be further discussed.

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“…These classical Hsp40 members assemble into homo-dimers through conserved C-terminal motifs and bind unfolded substrates through conserved β -barrel C-terminal domains (CTD) 20 . Recent evidence suggests that this subset of Hsp40s can form mixed hetero-dimers driven by electrostatic contacts to expand the substrate recognition repertoire 21 .…”

Section: Introductionmentioning

confidence: 99%

Auto-regulatory J-domain interactions control Hsp70 recruitment to the DnaJB8 chaperone

Ryder

Matlahov

Bali

et al. 2020

Preprint

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In humans, Hsp40s are classified into A, B, and C sub-families, in which members 90 typically function as monomers, dimers, or polydisperse oligomers. For example, the A 91 family Hsp40s (DnaJA1-A4) and a subset of B family Hsp40s (DnaJB1/B4/B5), all encode 92 a globular domain architecture similar to the bacterial Hsp40 DnaJ. These classical Hsp40 93 members assemble into homo-dimers through conserved C-terminal motifs and bind 94 unfolded substrates through conserved b-barrel C-terminal domains (CTD) 20 . Recent 95 evidence suggests that this subset of Hsp40s can form mixed hetero-dimers driven by 96 electrostatic contacts to expand the substrate recognition repertoire 21 . 97 98 A different set of non-classical Hsp40 B family members (DnaJB2, DnaJB6b, DnaJB7 and 99DnaJB8) encode a domain architecture that is distinct from the classical dimeric DnaJ 100 orthologs. Rather than encoding a classical b-barrel CTD, their C-terminus encodes a 101 different architecture [22][23] . Of these 4 members, the DnaJB8 and DnaJB6b proteins have 102 been shown to assemble into oligomers in vitro and in vivo 22,[24][25] . The role of the CTD in 103 these chaperones remains unclear, and the literature reveals conflicting results, 104 suggesting either that it drives oligomerization or that it mediates intramolecular 105 contacts [22][23][24] 26 . The functional role of the oligomeric state of DnaJB6b and DnaJB8 106 remains unclear, although it has been proposed to serve as a type of phase-separated 107 storage form capable of capturing substrates 25 . The characteristic structural and dynamic 108 heterogeneity of the oligomers has greatly hindered efforts to study them, with recent 109 structural studies resorting to deletion mutants to gain structural insight [22][23] . A 110 combination of variables, including large size and polydispersity, has made these 111 chaperones recalcitrant to both classical and modern structural biology methods, 112 including cryoEM 25 . 113 114 The oligomeric chaperones DnaJB6b and DnaJB8 have been shown to be potent 115 suppressors of aggregation of amyloid proteins in cells and in vitro 22, 26 . Despite several 116 studies demonstrating a role for DnaJB6b in suppressing assembly of amyloid-prone 117 substrates it is unclear which domains directly interact with substrates, and how 118 oligomerization plays a role in this process. For example, the serine/threonine domain of 119 DnaJB6b is important for suppression of mutant huntingtin protein aggregation in cells, 27 120 and its deletion limits oligomerization yielding a stable monomer at the expense of 121 activity 23 . In absence of a comprehensive understanding of the full-length structural 122 behavior for this class of DnaJ chaperones, it remains unclear how they fulfill their critical 123 function to protect the proteome from aggregation. 124 125Here we examine in unprecedented detail the DnaJB8 variant. DnaJB8 was shown to be 126 particularly effective at preventing formation of polyglutamine deposits, even more so than 127 DnaJB6b, despite...

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Evolution of an intricate J-protein network driving protein disaggregation in eukaryotes

Cited by 65 publications

References 81 publications

Recent advances in the structural and mechanistic aspects of Hsp70 molecular chaperones

Recent advances in the structural and mechanistic aspects of Hsp70 molecular chaperones

Repair or destruction—an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis

Auto-regulatory J-domain interactions control Hsp70 recruitment to the DnaJB8 chaperone

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