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

Abstract

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.

HSP70/DNAJ Family of Genes in the Brown Planthopper, Nilaparvata lugens: Diversity and Function

“…Consequently, though DNAJs play roles of cochaperones to their HSP70 partners, versatile biological roles independent of HSP70 were discovered in our study. More recently, accumulated evidence has uncovered a vast array of post-translational modifications on Hsp70 family proteins, including phosphorylation, methylation, acetylation, ubiquitination, AMPylation, and ADP-ribosylation [ 49 ]. As a result, differences in function of the HSP70/DNAJ machinery might arise from expression and sequence differences, as well as differential post-translational modification of HSP70 isoforms.…”

Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives

“…ARTC1 is a GPI anchored protein facing the extracellular space, which modifies T-cell co-receptors and circulating hemopexin, a heme transport protein [ 158 , 159 ]. ARTC1 is also present on membranes of intracellular compartments and modifies Grp78/BiP in ER, which dissociates from stress sensors [ 160 , 161 ]. Among heat shock proteins, Hsp70-5 (HSPA5/BiP/GRP78) is localized at the endoplasmic reticulum facilitating transport and folding of nascent polypeptides into the ER lumen.…”

Decrypting the chaperone code

“…The molecular chaperone heat shock protein 70 (Hsp70) is involved in folding, stability, and quality control of proteins ( 12 , 13 ). Hsp70 is also highly regulated by a range of PTMs ( 14 ). Dalia Barsyte-Lovejoy (University of Toronto, Canada) described how characterization of a novel inhibitor of the arginine methylase PRMT7 led to the discovery that Hsp70 is methylated on R469, a highly conserved amino acid present on the client-binding domain.…”