HSPA5
Description
The HSPA5 (heat shock protein family A (Hsp70) member 5) is a protein-coding gene located on chromosome 9.
Binding immunoglobulin protein (BiPS) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) is a protein that in humans is encoded by the HSPA5 gene. BiP is a HSP70 molecular chaperone located in the lumen of the endoplasmic reticulum (ER) that binds newly synthesized proteins as they are translocated into the ER, and maintains them in a state competent for subsequent folding and oligomerization. BiP is also an essential component of the translocation machinery and plays a role in retrograde transport across the ER membrane of aberrant proteins destined for degradation by the proteasome. BiP is an abundant protein under all growth conditions, but its synthesis is markedly induced under conditions that lead to the accumulation of unfolded polypeptides in the ER.
== Structure == BiP contains two functional domains: a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). The NBD binds and hydrolyzes ATP, and the SBD binds polypeptides. The NBD consists of two large globular subdomains (I and II), each further divided into two small subdomains (A and B). The subdomains are separated by a cleft where the nucleotide, one Mg2+, and two K+ ions bind and connect all four domains (IA, IB, IIA, IIB). The SBD is divided into two subdomains: SBDβ and SBDα. SBDβ serves as a binding pocket for client proteins or peptide and SBDα serves as a helical lid to cover the binding pocket. An inter-domain linker connects NBD and SBD, favoring the formation of an NBD–SBD interface.
HSPA5 is an endoplasmic reticulum chaperone that plays a key role in protein folding and quality control within the endoplasmic reticulum lumen. It assists in the proper folding of proteins and the degradation of misfolded proteins by interacting with DNAJC10/ERdj5, likely aiding in the release of DNAJC10/ERdj5 from its substrate. HSPA5 acts as a crucial repressor of the unfolded protein response (UPR) mediated by ERN1/IRE1. In unstressed conditions, it is recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, preventing the dimerization of ERN1/IRE1 and thereby inhibiting its activity. When misfolded proteins accumulate in the endoplasmic reticulum, HSPA5 is released from ERN1/IRE1, allowing its dimerization and subsequent activation. HSPA5 also plays a supporting role in the post-translational transport of small presecretory proteins across the endoplasmic reticulum (ER). It may act as an allosteric modulator for the SEC61 channel-forming translocon complex, potentially cooperating with SEC62 to facilitate the productive insertion of these precursors into the SEC61 channel. HSPA5 seems to specifically regulate the translocation of precursors containing inhibitory residues in their mature region that weaken channel gating. In addition, HSPA5 might be involved in apoptosis and cell proliferation.
HSPA5 is also known as BIP, GRP78, HEL-S-89n.
