scholarly journals On the evolution of chaperones and co-chaperones and the expansion of proteomes across the Tree of Life

2020 ◽  
Author(s):  
Mathieu E. Rebeaud ◽  
Saurav Mallik ◽  
Pierre Goloubinoff ◽  
Dan S. Tawfik
Keyword(s):  
Substrate Binding ◽  
Tree Of Life ◽  
Nucleotide Exchange ◽  
Systematic Analysis ◽  
Exchange Factor ◽  
Nucleotide Exchange Factor ◽  
Bacterial Proteomes

ABSTRACTAcross the Tree of Life (ToL), the complexity of proteomes varies widely. Our systematic analysis depicts that from the simplest archaea to mammals, the total number of proteins per proteome expanded ~200-fold. Individual proteins also became larger, and multi-domain proteins expanded ~50-fold. Apart from duplication and divergence of existing proteins, completely new proteins were born. Along the ToL, the number of different folds expanded ~5-fold and fold-combinations ~20-fold. Proteins prone to misfolding and aggregation, such as repeat and beta-rich proteins, proliferated ~600-fold, and accordingly, proteins predicted as aggregation-prone became 6-fold more frequent in mammalian compared to bacterial proteomes. To control the quality of these expanding proteomes, core-chaperones, ranging from HSP20s that prevent aggregation to HSP60, HSP70, HSP90, and HSP100 acting as ATP-fueled unfolding and refolding machines, also evolved. However, these core-chaperones were already available in prokaryotes, and they comprise ~0.3% of all genes from archaea to mammals. This challenge—roughly the same number of core-chaperones supporting a massive expansion of proteomes, was met by (i) higher cellular abundances of the ancient generalist core-chaperones, and (ii) continuous emergence of new substrate-binding and nucleotide-exchange factor co-chaperones that function cooperatively with core-chaperones, as a network.

scholarly journals On the evolution of chaperones and cochaperones and the expansion of proteomes across the Tree of Life

2021 ◽  
Vol 118 (21) ◽  
pp. e2020885118
Author(s):  
Mathieu E. Rebeaud ◽  
Saurav Mallik ◽  
Pierre Goloubinoff ◽  
Dan S. Tawfik
Keyword(s):  
Heat Shock ◽  
Messenger Rna ◽  
Tree Of Life ◽  
Nucleotide Exchange ◽  
Multidomain Proteins ◽  
Systematic Analysis ◽  
Nucleotide Exchange Factor ◽  
Shock Proteins ◽  
Bacterial Proteomes

Across the Tree of Life (ToL), the complexity of proteomes varies widely. Our systematic analysis depicts that from the simplest archaea to mammals, the total number of proteins per proteome expanded ∼200-fold. Individual proteins also became larger, and multidomain proteins expanded ∼50-fold. Apart from duplication and divergence of existing proteins, completely new proteins were born. Along the ToL, the number of different folds expanded ∼5-fold and fold combinations ∼20-fold. Proteins prone to misfolding and aggregation, such as repeat and beta-rich proteins, proliferated ∼600-fold and, accordingly, proteins predicted as aggregation-prone became 6-fold more frequent in mammalian compared with bacterial proteomes. To control the quality of these expanding proteomes, core chaperones, ranging from heat shock proteins 20 (HSP20s) that prevent aggregation to HSP60, HSP70, HSP90, and HSP100 acting as adenosine triphosphate (ATP)-fueled unfolding and refolding machines, also evolved. However, these core chaperones were already available in prokaryotes, and they comprise ∼0.3% of all genes from archaea to mammals. This challenge—roughly the same number of core chaperones supporting a massive expansion of proteomes—was met by 1) elevation of messenger RNA (mRNA) and protein abundances of the ancient generalist core chaperones in the cell, and 2) continuous emergence of new substrate-binding and nucleotide-exchange factor cochaperones that function cooperatively with core chaperones as a network.

scholarly journals Propagation of Saccharomyces cerevisiae [PSI+] Prion Is Impaired by Factors That Regulate Hsp70 Substrate Binding

2004 ◽  
Vol 24 (9) ◽  
pp. 3928-3937 ◽  
Author(s):  
Gary Jones ◽  
Youtao Song ◽  
Seyung Chung ◽  
Daniel C. Masison
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Substrate Binding ◽  
Tetratricopeptide Repeat ◽  
Physical Interaction ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Nucleotide Exchange Factor

ABSTRACT The Saccharomyces cerevisiae [PSI+ ] prion is believed to be a self-propagating cytoplasmic amyloid. Earlier characterization of HSP70 (SSA1) mutations suggested that [PSI+ ] propagation is impaired by alterations that enhance Ssa1p's substrate binding. This impairment is overcome by second-site mutations in Ssa1p's conserved C-terminal motif (GPTVEEVD), which mediates interactions with tetratricopeptide repeat (TPR) cochaperones. Sti1p, a TPR cochaperone homolog of mammalian Hop1 (Hsp70/90 organizing protein), activates Ssa1p ATPase, which promotes substrate binding by Ssa1p. Here we find that in SSA1-21 cells depletion of Sti1p improved [PSI +] propagation, while excess Sti1p weakened it. In contrast, depletion of Fes1p, a nucleotide exchange factor for Ssa1p that facilitates substrate release, weakened [PSI +] propagation, while overproducing Fes1p improved it. Therefore, alterations of Hsp70 cochaperones that promote or prolong Hsp70 substrate binding impair [PSI +] propagation. We also find that the GPTVEEVD motif is important for physical interaction with Hsp40 (Ydj1p), another Hsp70 cochaperone that promotes substrate binding but is dispensable for viability. We further find that depleting Cpr7p, an Hsp90 TPR cochaperone and CyP-40 cyclophilin homolog, improved [PSI +] propagation in SSA1 mutants. Although Cpr7p and Sti1p are Hsp90 cochaperones, we provide evidence that Hsp90 is not involved in [PSI +] propagation, suggesting that Sti1p and Cpr7p functionally interact with Hsp70 independently of Hsp90.

scholarly journals Substrate binding by the yeast Hsp110 nucleotide exchange factor and molecular chaperone Sse1 is not obligate for its biological activities

2017 ◽  
Vol 28 (15) ◽  
pp. 2066-2075 ◽  
Author(s):  
Veronica M. Garcia ◽  
Nadinath B. Nillegoda ◽  
Bernd Bukau ◽  
Kevin A. Morano
Keyword(s):  
Molecular Chaperone ◽  
Biological Activities ◽  
Substrate Binding ◽  
Normal Growth ◽  
Cellular Protein ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Nucleotide Exchange Factor

The highly conserved heat shock protein 70 (Hsp70) is a ubiquitous molecular chaperone essential for maintaining cellular protein homeostasis. The related protein Hsp110 (Sse1/Sse2 in Saccharomyces cerevisiae) functions as a nucleotide exchange factor (NEF) to regulate the protein folding activity of Hsp70. Hsp110/Sse1 also can prevent protein aggregation in vitro via its substrate-binding domain (SBD), but the cellular roles of this “holdase” activity are poorly defined. We generated and characterized an Sse1 mutant that separates, for the first time, its nucleotide exchange and substrate-binding functions. Sse1sbd retains nucleotide-binding and nucleotide exchange activities while exhibiting severe deficiencies in chaperone holdase activity for unfolded polypeptides. In contrast, we observed no effect of the SBD mutation in reconstituted disaggregation or refolding reactions in vitro. In vivo, Sse1sbd successfully heterodimerized with the yeast cytosolic Hsp70s Ssa and Ssb and promoted normal growth, with the exception of sensitivity to prolonged heat but not other proteotoxic stress. Moreover, Sse1sbd was fully competent to support Hsp90-dependent signaling through heterologously expressed glucocorticoid receptor and degradation of a permanently misfolded protein, two previously defined roles for Sse1. We conclude that despite conservation among eukaryotic homologues, chaperone holdase activity is not an obligate function in the Hsp110 family.

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