CHIP/STUB1: Proteins and Enzymes

STIP1 Homology and U-box Containing Protein 1 (STUB1), also known as Carboxyl Terminus of Hsp70-interacting Protein (CHIP), is a cytoplasmic protein that functions as a U-box Ubiquitin ligase (E3). It is highly expressed in striated muscle and brain and has been observed at lower levels in other organs including the pancreas, lung, liver, and kidney. STUB1/CHIP is 303 amino acids (aa) in length with a predicted molecular weight of 34.8 kDa. Human STUB1/CHIP shares 97% aa sequence identity with the mouse ortholog but only 67% sequence identity with the rat ortholog. It consists of three 34 aa N-terminal tetratricopeptide repeat (TRP) domains (aa 26-127) that are responsible for protein-protein interactions and a C-terminal U-box domain (aa 226-300) that participates in ubiquitination. A central domain containing charged residues lies between the TRP and U-box domains and is thought to be necessary for TRP-dependent interactions. STUB1/CHIP participates in intracellular protein folding/refolding and degradation. It complexes with several molecular chaperone proteins, including HSP70/HSPA1A, HSC70, and HSP90, and modulates their activity. It also facilitates the ubiquitination of chaperone substrates, including nascent CFTR, phosphorylated Tau, p53, PTEN, Synuclein-alpha, and beta-APP, promoting their degradation.