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 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 Disaggregases, molecular chaperones that resolubilize protein aggregates

2015 ◽  
Vol 87 (2 suppl) ◽  
pp. 1273-1292 ◽  
Author(s):  
David Z. Mokry ◽  
Josielle Abrahão ◽  
Carlos H.I. Ramos
Keyword(s):  
Heat Shock ◽  
Molecular Chaperones ◽  
Protein Function ◽  
Protein Aggregates ◽  
Cell Physiology ◽  
Biological Processes ◽  
Loss Of Function ◽  
Prion Propagation ◽  
Shock Proteins

The process of folding is a seminal event in the life of a protein, as it is essential for proper protein function and therefore cell physiology. Inappropriate folding, or misfolding, can not only lead to loss of function, but also to the formation of protein aggregates, an insoluble association of polypeptides that harm cell physiology, either by themselves or in the process of formation. Several biological processes have evolved to prevent and eliminate the existence of non-functional and amyloidogenic aggregates, as they are associated with several human pathologies. Molecular chaperones and heat shock proteins are specialized in controlling the quality of the proteins in the cell, specifically by aiding proper folding, and dissolution and clearance of already formed protein aggregates. The latter is a function of disaggregases, mainly represented by the ClpB/Hsp104 subfamily of molecular chaperones, that are ubiquitous in all organisms but, surprisingly, have no orthologs in the cytosol of metazoan cells. This review aims to describe the characteristics of disaggregases and to discuss the function of yeast Hsp104, a disaggregase that is also involved in prion propagation and inheritance.

scholarly journals Roles of the nucleotide exchange factor and chaperone Hsp110 in cellular proteostasis and diseases of protein misfolding

2018 ◽  
Vol 399 (10) ◽  
pp. 1215-1221 ◽  
Author(s):  
Unekwu M. Yakubu ◽  
Kevin A. Morano
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Recent Progress ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Nucleotide Exchange Factor

Abstract Cellular protein homeostasis (proteostasis) is maintained by a broad network of proteins involved in synthesis, folding, triage, repair and degradation. Chief among these are molecular chaperones and their cofactors that act as powerful protein remodelers. The growing realization that many human pathologies are fundamentally diseases of protein misfolding (proteopathies) has generated interest in understanding how the proteostasis network impacts onset and progression of these diseases. In this minireview, we highlight recent progress in understanding the enigmatic Hsp110 class of heat shock protein that acts as both a potent nucleotide exchange factor to regulate activity of the foldase Hsp70, and as a passive chaperone capable of recognizing and binding cellular substrates on its own, and its integration into the proteostasis network.

scholarly journals Reversible Thermal Transition in GrpE, the Nucleotide Exchange Factor of the DnaK Heat-Shock System

2000 ◽  
Vol 276 (9) ◽  
pp. 6098-6104 ◽  
Author(s):  
John P. A. Grimshaw ◽  
Ilian Jelesarov ◽  
Hans-Joachim Schönfeld ◽  
Philipp Christen
Keyword(s):  
Heat Shock ◽  
Thermal Transition ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Nucleotide Exchange Factor ◽  
Shock System

A Role for the Noncatalytic N Terminus in the Function of Cdc25, a Saccharomyces cerevisiae Ras-Guanine Nucleotide Exchange Factor

Genetics ◽  
2000 ◽  
Vol 154 (4) ◽  
pp. 1473-1484
Author(s):  
Reneé A Chen ◽  
Tamer Michaeli ◽  
Linda Van Aelst ◽  
Roymarie Ballester
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Heat Shock ◽  
Guanine Nucleotide Exchange Factor ◽  
Dominant Negative ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Ras Pathway ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
N Terminus

Abstract The Saccharomyces cerevisiae CDC25 gene encodes a guanine nucleotide exchange factor (GEF) for Ras proteins. Its catalytic domain is highly homologous to Ras-GEFs from all eukaryotes. Even though Cdc25 is the first Ras-GEF identified in any organism, we still know very little about how its function is regulated in yeast. In this work we provide evidence for the involvement of the N terminus of Cdc25 in the regulation of its activity. A truncated CDC25 lacking the noncatalytic C-terminal coding sequence was identified in a screen of high-copy suppressors of the heat-shock-sensitive phenotype of strains in which the Ras pathway is hyper-activated. The truncated gene acts as a dominant-negative mutant because it only suppresses the heat-shock sensitivity of strains that require the function of CDC25. Our two-hybrid assays and immunoprecipitation analyses show interactions between the N terminus of Cdc25 and itself, the C terminus, and the full-length protein. These results suggest that the dominant-negative effect may be a result of oligomerization with endogenous Cdc25. Further evidence of the role of the N terminus of Cdc25 in the regulation of its activity is provided by the mapping of the activating mutation of CDC25HS20 to the serine residue at position 365 in the noncatalytic N-terminal domain. This mutation induces a phenotype similar to activating mutants of other genes in the Ras pathway in yeast. Hence, the N terminus may exert a negative control on the catalytic activity of the protein. Taken together these results suggest that the N terminus plays a crucial role in regulating Cdc25 and consequently Ras activity, which in S. cerevisiae is essential for cell cycle progression.

scholarly journals Up-regulated cytotrophoblast DOCK4 contributes to over-invasion in placenta accreta spectrum

2020 ◽  
Vol 117 (27) ◽  
pp. 15852-15861
Author(s):  
Leah McNally ◽  
Yan Zhou ◽  
Joshua F. Robinson ◽  
Guangfeng Zhao ◽  
Lee-may Chen ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Placenta Accreta ◽  
Expression Patterns ◽  
Rare Condition ◽  
Global Gene Expression ◽  
Nucleotide Exchange ◽  
Altered Expression ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Placenta Accreta Spectrum

In humans, a subset of placental cytotrophoblasts (CTBs) invades the uterus and its vasculature, anchoring the pregnancy and ensuring adequate blood flow to the fetus. Appropriate depth is critical. Shallow invasion increases the risk of pregnancy complications, e.g., severe preeclampsia. Overly deep invasion, the hallmark of placenta accreta spectrum (PAS), increases the risk of preterm delivery, hemorrhage, and death. Previously a rare condition, the incidence of PAS has increased to 1:731 pregnancies, likely due to the rise in uterine surgeries (e.g., Cesarean sections). CTBs track along scars deep into the myometrium and beyond. Here we compared the global gene expression patterns of CTBs from PAS cases to gestational age-matched control cells that invaded to the normal depth from preterm birth (PTB) deliveries. The messenger RNA (mRNA) encoding the guanine nucleotide exchange factor,DOCK4, mutations of which promote cancer cell invasion and angiogenesis, was the most highly up-regulated molecule in PAS samples. Overexpression ofDOCK4increased CTB invasiveness, consistent with the PAS phenotype. Also, this analysis identified other genes with significantly altered expression in this disorder, potential biomarkers. These data suggest that CTBs from PAS cases up-regulate a cancer-like proinvasion mechanism, suggesting molecular as well as phenotypic similarities in the two pathologies.

scholarly journals Pharmacology of natural radioprotectors

2018 ◽  
Vol 41 (11) ◽  
pp. 1033-1050 ◽  
Author(s):  
Gil-Im Mun ◽  
Seoyoung Kim ◽  
Eun Choi ◽  
Cha Soon Kim ◽  
Yun-Sil Lee
Keyword(s):  
Quality Of Life ◽  
Free Radical ◽  
Heat Shock ◽  
Radical Scavenging ◽  
Free Radical Scavenging ◽  
Naturally Occurring ◽  
Radiation Induced ◽  
Shock Proteins ◽  
Radioprotective Properties

Abstract Radiotherapy is one of the most efficient ways to treat cancer. However, deleterious effects, such as acute and chronic toxicities that reduce the quality of life, may result. Naturally occurring compounds have been shown to be non-toxic over wide dose ranges and are inexpensive and effective. Additionally, pharmacological strategies have been developed that use radioprotectors to inhibit radiation-induced toxicities. Currently available radioprotectors have several limitations, including toxicity. In this review, we present the mechanisms of proven radioprotectors, ranging from free radical scavenging (the best-known mechanism of radioprotection) to molecular-based radioprotection (e.g., upregulating expression of heat shock proteins). Finally, we discuss naturally occurring compounds with radioprotective properties in the context of these mechanisms.

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