The heat shock protein 70(Hsp70)family of molecular chaperones is essential for nearly every cell to support protein homeostasis through folding,signaling,and quality control.Hsp70 functionality critically depends on ...The heat shock protein 70(Hsp70)family of molecular chaperones is essential for nearly every cell to support protein homeostasis through folding,signaling,and quality control.Hsp70 functionality critically depends on co-chaperones,including the GrpE-like family of nucleotide exchange factors(NEFs),first identified in Escherichia coli as GrpE.These factors have long been recognized for their ability to catalyze the release of Hsp70 nucleotide and protein substrates,but recent structural and functional studies have revealed that GrpE-like NEFs are more than passive exchange catalysts,instead acting as dynamic regulators that coordinate chaperone activity with cellular stress responses,organelle-specific demands,and allosteric control of substrate binding and release.In this review,we synthesize decades of research on GrpE-like proteins across bacteria and eukaryotes,culminating in high-resolution structures of the human mitochondrial NEF,GrpEL1,in complex with mitochondrial Hsp70.We examine how architectural features of GrpE-like NEFs have evolved to meet specialized demands,such as thermosensing in bacteria,redox-responsive regulation in vertebrates,and coordination of protein import in mitochondria.We further describe how discrete structural domains dynamically control chaperone cycling,including nucleotide and substrate release,and how gene duplication and domain specialization have driven functional diversification in higher eukaryotes.Finally,we highlight emerging evidence linking NEF activity to mitochondrial homeostasis,stress adaptation,and disease,reframing GrpE-like NEFs as tunable regulators rather than static cofactors.This perspective positions them as stress-adaptive control points in proteostasis and offers a conceptual framework for understanding how ancient chaperone systems have evolved to meet the regulatory needs of modern and complex eukaryotic cells.展开更多
Abstract Heat shock proteins （Hsps）, produced by organisms under high temperature stimulation, play important roles in protein folding, translocation, and refolding/degradati0n. In this study, we investigated the ex...Abstract Heat shock proteins （Hsps）, produced by organisms under high temperature stimulation, play important roles in protein folding, translocation, and refolding/degradati0n. In this study, we investigated the expression level of the GrpE Hsp gene Hsp845 of Psychrobacter sp. G under different temperature and salinity stresses by quantitative real-time PCR and western blotting, respectively. At both transcriptional and translational levels, Hsp845 gene expression was induced by high temperature （30~C） and inhibited by low temperatures （0~C and 10~C）. Hsp845 expression was also induced both by the absence of salt （0%0） and high salinity （90%0 and 120%o） at the transcriptional level, but was only induced by high salinity （90%0 and 120%o） at the translational level. In a combined stress treatment, Hsp845 was more sensitive to high temperature than to salinity at both transcriptional and translational levels. The increase in the translational-level expression of Hsp845 lagged behind that at the transcriptional level, and Hsp845 maximum expression was also higher at the transcriptional than at the translational level. In the absence of salt, transcriptional- and translational-level expressions exhibited opposite patterns, suggesting that the underlying mechanism requires further study.展开更多
基金support from the National Institutes of Health(NIH)grant R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology,National Institute of Allergy and Infectious Dis easesfunded by the NIH(R35-GM138206 to M.A.H.,T32-GM008326 to M.A.M.),as well as the Searle Scholars Program(M.A.H.),the Cottrell Scholars Program(M.A.H.),and the UCSD’s Triton Research&Experiential Learning Scholars(TRELS)Program(T.V.S.).
文摘The heat shock protein 70(Hsp70)family of molecular chaperones is essential for nearly every cell to support protein homeostasis through folding,signaling,and quality control.Hsp70 functionality critically depends on co-chaperones,including the GrpE-like family of nucleotide exchange factors(NEFs),first identified in Escherichia coli as GrpE.These factors have long been recognized for their ability to catalyze the release of Hsp70 nucleotide and protein substrates,but recent structural and functional studies have revealed that GrpE-like NEFs are more than passive exchange catalysts,instead acting as dynamic regulators that coordinate chaperone activity with cellular stress responses,organelle-specific demands,and allosteric control of substrate binding and release.In this review,we synthesize decades of research on GrpE-like proteins across bacteria and eukaryotes,culminating in high-resolution structures of the human mitochondrial NEF,GrpEL1,in complex with mitochondrial Hsp70.We examine how architectural features of GrpE-like NEFs have evolved to meet specialized demands,such as thermosensing in bacteria,redox-responsive regulation in vertebrates,and coordination of protein import in mitochondria.We further describe how discrete structural domains dynamically control chaperone cycling,including nucleotide and substrate release,and how gene duplication and domain specialization have driven functional diversification in higher eukaryotes.Finally,we highlight emerging evidence linking NEF activity to mitochondrial homeostasis,stress adaptation,and disease,reframing GrpE-like NEFs as tunable regulators rather than static cofactors.This perspective positions them as stress-adaptive control points in proteostasis and offers a conceptual framework for understanding how ancient chaperone systems have evolved to meet the regulatory needs of modern and complex eukaryotic cells.
基金supported financially by the National Natural Science Foundation of China (Grant no.41176174)
文摘Abstract Heat shock proteins （Hsps）, produced by organisms under high temperature stimulation, play important roles in protein folding, translocation, and refolding/degradati0n. In this study, we investigated the expression level of the GrpE Hsp gene Hsp845 of Psychrobacter sp. G under different temperature and salinity stresses by quantitative real-time PCR and western blotting, respectively. At both transcriptional and translational levels, Hsp845 gene expression was induced by high temperature （30~C） and inhibited by low temperatures （0~C and 10~C）. Hsp845 expression was also induced both by the absence of salt （0%0） and high salinity （90%0 and 120%o） at the transcriptional level, but was only induced by high salinity （90%0 and 120%o） at the translational level. In a combined stress treatment, Hsp845 was more sensitive to high temperature than to salinity at both transcriptional and translational levels. The increase in the translational-level expression of Hsp845 lagged behind that at the transcriptional level, and Hsp845 maximum expression was also higher at the transcriptional than at the translational level. In the absence of salt, transcriptional- and translational-level expressions exhibited opposite patterns, suggesting that the underlying mechanism requires further study.
