The carboxy terminus of Hsc70-interacting protein (CHIP, STUB1) is a co-chaperone protein and functional E3 ubiquitin ligase that links the polypeptide binding activity of Hsp70 to the ubiquitin proteasome system (1). Cytoplasmic CHIP protein contains three 34-amino acid TPR (tetratricopeptide repeat) domains at its amino terminus and a carboxy-terminal U-box domain. CHIP interacts with the molecular chaperones Hsc70-Hsp70 and Hsp90 through its TPR domain, while E3 ubiquitin ligase activity is confined to the U-box domain (2,3). The binding of CHIP to Hsp70 can stall the folding of Hsp70 client proteins and concomitantly facilitate the U-box dependent ubiquitination of Hsp70-bound substrates (4-6). CHIP appears to play a central role in cell stress protection (7) and is responsible for the degradation of disease-related proteins that include cystic fibrosis transmembrane conductance regulator (4), p53 (8), huntingtin and Ataxin-3 (9), Tau protein (10), and α-synuclein (11).
