The E3 ligase CHIP: insights into its structure and regulation.

Indranil Paul,Mrinal K Ghosh

doi:10.1155/2014/918183

Abstract

The carboxy-terminus of Hsc70 interacting protein (CHIP) is a cochaperone E3 ligase containing three tandem repeats of tetratricopeptide (TPR) motifs and a C-terminal U-box domain separated by a charged coiled-coil region. CHIP is known to function as a central quality control E3 ligase and regulates several proteins involved in a myriad of physiological and pathological processes. Recent studies have highlighted varied regulatory mechanisms operating on the activity of CHIP which is crucial for cellular homeostasis. In this review article, we give a concise account of our current knowledge on the biochemistry and regulation of CHIP.

Highlights

Maintaining the integrity of the proteome is essential for normal cellular functions
The matured form of a given protein remains in a dubious equilibrium, often misfolding to various degrees during its lifespan, as a result of stochastic fluctuations, presence of destabilizing mutations, stress conditions, or unique metabolic challenges, such as cancer or aging
Predictive of its Ubox, carboxy-terminus of Hsc70 interacting protein (CHIP) was identified as the first chaperone associated E3 ligase that targets Hsp90 and Hsp70 clients for degradation through the 26S proteasome [6,7,8,9] and is suggested to be involved in substrate delivery to the proteasome [6, 10]

Summary

Introduction

Maintaining the integrity of the proteome is essential for normal cellular functions. It was found to be highly expressed in tissues (such as skeletal muscle) with high metabolic activity and protein turnover [2]. This dual-function cochaperone/E3 ligase protein activates HSF1 under various stress conditions and confers protection against apoptosis. Predictive of its Ubox, CHIP was identified as the first chaperone associated E3 ligase that targets Hsp (partially folded) and Hsp (misfolded) clients for degradation through the 26S proteasome [6,7,8,9] and is suggested to be involved in substrate delivery to the proteasome [6, 10].

Initial Discovery and Characterization

Structural Organization of CHIP

CHIP Is Regulated at the Transcriptional and Posttranscriptional Levels

Future Directions