Regulation of molecular chaperones through post-translational modifications: decrypting the chaperone code

Abstract

Molecular chaperones and their associated cofactors form a group of highly specialized proteins that orchestrate the folding and unfolding of other proteins and the assembly and disassembly of protein complexes. Chaperones are found in all cell types and organisms, and their activity must be tightly regulated to maintain normal cell function. Indeed, deregulation of protein folding and protein complex assembly is the cause of various human diseases. Here, we present the results of an extensive review of the literature revealing that the post-translational modification (PTM) of chaperones has been selected during evolution as an efficient mean to regulate the activity and specificity of these key proteins. Because the addition and reciprocal removal of chemical groups can be triggered very rapidly, this mechanism provides an efficient switch to precisely regulate the activity of chaperones on specific substrates. The large number of PTMs detected in chaperones suggests that a combinatory code is at play to regulate function, activity, localization, and substrate specificity for this group of biologically important proteins. This review surveys the core information currently available as a starting point toward the more ambitious endeavor of deciphering the "chaperone code".

Fig. 1

Hsp70 and Hsc70 post-translational modifications. Linear representation of the Hsp70 and Hsc70 isoforms of the Hsp70 family with ATPase domain, substrate binding domain (SBD) and C-terminal EEVD motif. All reported PTMs are marked according to a color code: tyrosine phosphorylation (Y-P) in dark blue, threonine phosphorylation (T-P) in light blue, serine phosphorylation (S-P) in green, ubiquitination (U) in red, acetylation (A) in orange and all others modifications in purple. Methylation (M) of arginine or lysine residues are the only infrequent modifications indexed in this instance. The majority of the data was provided by the public PTM database PhosphoSitePlus (http://www.phosphosite.org) and also from various sources in the scientific literature. PTMs identified on the basis of a single mass spectrum or reported in a single article are denoted with an asterisk.

Fig. 2

Hsp90α and Hsp90β post-translational modifications. Linear representation of the Hsp90α and Hsp90β isoforms of the Hsp90 family with N-terminal ATPase domain, middle (M) domain, C-terminal dimerization (C) domain and EEVD motif. All reported PTMs are marked according to a color code: tyrosine phosphorylation (Y-P) in dark blue, threonine phosphorylation (T-P) in light blue, serine phosphorylation (S-P) in green, ubiquitination (U) in red, acetylation (A) in orange and all others modifications in purple. Lysine methylation (M), glycosylation (G) and S-thionylation (T; a broad term which serves to describe a number of redox modifications that take place on the sulfur group of cysteine residues including disulfide oxidation, S-nitrosylation and S-glutathionylation) are among the infrequent modifications reported here. The majority of the data was provided by the public PTM database PhosphoSitePlus (http://www.phosphosite.org) and also from various sources in the scientific literature. PTMs identified on the basis of a single mass spectrum or reported in a single article are denoted with an asterisk.

Fig. 3

VCP/p97 post-translational modifications. Linear representation of the VCP/p97 protein with N-terminal (N) domain and dual ATPase domains D1 and D2. All reported PTMs are marked according to a color code: tyrosine phosphorylation (Y-P) in dark blue, threonine phosphorylation (T-P) in light blue, serine phosphorylation (S-P) in green, ubiquitination (U) in red, acetylation (A) in orange and all others modifications in purple. Lysine methylation (M) and S-thionylation (T; a broad term which serves to describe a number of redox modifications that take place on the sulfur group of cysteine residues including disulfide oxidation, S-nitrosylation and S-glutathionylation) are among the infrequent modifications reported here. The majority of the data was provided by the public PTM database PhosphoSitePlus (http://www.phosphosite.org) and also from various sources in the scientific literature. PTMs identified on the basis of a single mass spectrum or reported in a single article are denoted with an asterisk.

Fig. 4

Schematic representation of the chaperone code. The post-translational modification (PTM) of molecular chaperones, through phosphorylation (P), acetylation (A), ubiquitination (U), methylation (M) and other chemical modifications, represents a widely used cellular strategy to regulate, with extreme rapidity and precision, the activity of these proteins that orchestrate protein folding/unfolding and protein complex assembly/disassembly. PTMs have been shown to modulate various aspects of chaperone function, including enzymatic activity (ATPase activity for Hsp90, Hsp70 and VCP), co-factor binding and protein client binding that together control chaperone specificity, and transporter binding that has the ability to relocalize chaperones in a cellular compartment where they can exert a distinct function by binding new cochaperones and client proteins. The notion of a chaperone code helps explaining how, by combining specific PTMs, a given molecular chaperone can discriminate between a multitude of substrates to respond efficiently to changing needs within the cell, both in a time and space controlled manner.