This entry includes human endoplasmic reticulum chaperone BIP (also known as 70kDa heat shock protein 5, HSPA5, glucose-regulated protein 78/GRP78, and immunoglobulin heavy chain-binding protein), yeast Kar2p (also known as Grp78p) [, ], hsp-3 from C. elegans []and related proteins. BIP/HSPA5 belongs to the heat shock protein 70 (HSP70) family of chaperones that assist in protein folding and assembly and can direct incompetent 'client' proteins towards degradation. HSPA5 and Kar2p are chaperones of the endoplasmic reticulum (ER). Typically, HSP70s have a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). The nucleotide sits in a deep cleft formed between the two lobes of the NBD. The two subdomains of each lobe change conformation between ATP-bound, ADP-bound, and nucleotide-free states. ATP binding opens up the substrate-binding site; substrate-binding increases the rate of ATP hydrolysis. HSP70 chaperone activity is regulated by various co-chaperones: J-domain proteins and nucleotide exchange factors (NEFs). Multiple ER DNAJ domain proteins have been identified and may exist in distinct complexes with HSPA5 in various locations in the ER, for example DNAJC3-p58IPK in the lumen []. HSPA5-NEFs include SIL1, whose disruption causes the Marinesco-Sjogren syndrome, and an atypical HSP70 family protein HYOU1/ORP150 [, ]. The ATPase activity of Kar2p is stimulated by the NEFs: Sil1p and Lhs1p [].
