Not quite the SSAme: unique roles for the yeast cytosolic Hsp70s

Lotz, Sarah K.; Knighton, Laura E.; Nitika, .; Jones, Gary W.; Truman, Andrew W.

doi:10.1007/s00294-019-00978-8

Cited by 32 publications

(51 citation statements)

References 61 publications

(84 reference statements)

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“…Recent studies clearly demonstrate that human Hsp70 variants display differential preferences for clients and co-chaperones (180,181). These studies are corroborated by functional studies in yeast that reveal phenotypic differences in yeast expressing single Ssa isoforms (23,(182)(183)(184)(185). Taken together, the data suggest that cytoplasmic Hsp70 variants have overlapping but distinct client-binding specificities driving unique roles in the cell.…”

Section: Conservation Of Ptm Sites Between Hsp70 Isoformsmentioning

confidence: 73%

“…S. cerevisiae contains seven cytosolic Hsp70 isoforms: the four canonical chaperones Ssa1, Ssa2, Ssa3, and Ssa4 and the three ribosomeassociated chaperones Ssb1, Ssb2, and Ssz1. In addition, there are three mitochondrial isoforms (Ssc1, Ssq1, and Ecm10) and one specific to endoplasmic reticulum (Kar2) (23). Ssa1 and Ssa2 are constitutively expressed, whereas Ssa3 and Ssa4 are not present during normal growth but up-regulated in response to stress and in the stationary phase (24)(25)(26)(27).…”

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confidence: 99%

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Post-translational modifications of Hsp70 family proteins: Expanding the chaperone code

Nitika

Porter

Truman

et al. 2020

Journal of Biological Chemistry

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118

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Cells must be able to cope with the challenge of folding newly synthesized proteins and refolding those that have become misfolded in the context of a crowded cytosol. One such coping mechanism that has appeared during evolution is the expression of well-conserved molecular chaperones, such as those that are part of the heat shock protein 70 (Hsp70) family of proteins that bind and fold a large proportion of the proteome. Although Hsp70 family chaperones have been extensively examined for the last 50 years, most studies have focused on regulation of Hsp70 activities by altered transcription, co-chaperone “helper” proteins, and ATP binding and hydrolysis. The rise of modern proteomics has uncovered a vast array of post-translational modifications (PTMs) on Hsp70 family proteins that include phosphorylation, acetylation, ubiquitination, AMPylation, and ADP-ribosylation. Similarly to the pattern of histone modifications, the histone code, this complex pattern of chaperone PTMs is now known as the “Chaperone Code.” In this review, we discuss the history of the Hsp70 chaperone code, its currently understood regulation and functions, as well as thoughts on what the future of research into the chaperone code may entail.

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Section: Conservation Of Ptm Sites Between Hsp70 Isoformsmentioning

confidence: 73%

mentioning

confidence: 99%

Post-translational modifications of Hsp70 family proteins: Expanding the chaperone code

Nitika

Porter

Truman

et al. 2020

Journal of Biological Chemistry

Self Cite

118

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“…Due to their high conservation both in evolution and within the Hsp70 family, (human) Hsp70 proteins are often regarded as largely interchangeable (12)(13)(14)(15)(16)(17). However, specificity between Hsp70 machines does exist and different effects of the various Hsp70s have been reported (6,8,(18)(19)(20). The recognition of substrates by Hsp70 is quite generic and since there is a lot more variability in JDPs and NEFs, the last two families have been suggested as the ones that confer specificity to the Hsp70 system (8).…”

mentioning

confidence: 99%

Functional diversity between HSP70 paralogs caused by variable interactions with specific co-chaperones

Serlidaki

Rohland

Wentink

et al. 2020

Journal of Biological Chemistry

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Heat shock protein 70 (HSP70) chaperones play a central role in protein quality control and are crucial for many cellular processes, including protein folding, degradation, and disaggregation. Human HSP70s compose a family of 13 members that carry out their functions with the aid of even larger families of co-chaperones. A delicate interplay between HSP70s and co-chaperone recruitment is thought to determine substrate fate, yet it has been generally assumed that all Hsp70 paralogs have similar activities and are largely functionally redundant. However, here we found that when expressed in human cells, two highly homologous HSP70s, HSPA1A and HSPA1L, have opposing effects on cellular handling of various substrates. For example, HSPA1A reduced aggregation of the amyotrophic lateral sclerosis–associated protein variant superoxide dismutase 1 (SOD1)–A4V, whereas HSPA1L enhanced its aggregation. Intriguingly, variations in the substrate-binding domain of these HSP70s did not play a role in this difference. Instead, we observed that substrate fate is determined by differential interactions of the HSP70s with co-chaperones. Whereas most co-chaperones bound equally well to these two HSP70s, Hsp70/Hsp90-organizing protein (HOP) preferentially bound to HSPA1L, and the Hsp110 nucleotide-exchange factor HSPH2 preferred HSPA1A. The role of HSPH2 was especially crucial for the HSPA1A-mediated reduction in SOD1-A4V aggregation. These findings reveal a remarkable functional diversity at the level of the cellular HSP70s and indicate that this diversity is defined by their affinities for specific co-chaperones such as HSPH2.

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“…As evident from the the dramatic diversification of chaperone families with increasing organism complexity (13), individual chaperones with their specific interactions likely play a key role in the selective regulation of cellular networks (85). Even seeming similar chaperones have been found with unique roles and distinct specialization given the right context (86). This thinking is also supported by the findings that functional innovation through gene duplication often equally rests on increased fidelity of regulation (89).…”

Section: Discussionmentioning

confidence: 86%

Programmed trade-offs in protein folding networks

Pechmann

2020

Preprint

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Maintaining protein homeostasis, i.e. a folded and functional proteome, depends on the efficient allocation of cellular protein quality control resources. Decline and dysregulation of protein homeostasis are directly associated to conditions of aging and neurodegeneration. Molecular chaperones as specialized protein quality control enzymes form the core of protein homeostasis. However, how chaperones selectively interact with their substrate proteins thus allocate their overall limited capacity remains poorly understood. Here, I present an integrated analysis of sequence and structural determinants that define interactions of the Saccharomyces cerevisiae Hsp70 Ssb. Structural homologues that differentially interact with Ssb for de novo folding were found to systematically differ in complexity of their folding landscapes, selective use of nonoptimal codons, and presence of short discriminative sequences. All analyzed characteristics contributed to the prediction of Ssb interactions in highly complementary manner, highlighting pervasive trade-offs in chaperone-assisted protein folding landscapes. However, short discriminative sequences were found to contribute by far the strongest signal towards explaining Ssb interactions. This observation suggested that some chaperone interactions may be directly programmed in the amino acid sequences rather than responding to folding challenges, possibly for regulatory advantages.

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Not quite the SSAme: unique roles for the yeast cytosolic Hsp70s

Cited by 32 publications

References 61 publications

Post-translational modifications of Hsp70 family proteins: Expanding the chaperone code

Post-translational modifications of Hsp70 family proteins: Expanding the chaperone code

Functional diversity between HSP70 paralogs caused by variable interactions with specific co-chaperones

Programmed trade-offs in protein folding networks

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