HSPA8
Description
The HSPA8 (heat shock protein family A (Hsp70) member 8) is a protein-coding gene located on chromosome 11.
Heat shock 70 kDa protein 8, also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73, is a heat shock protein that in humans is encoded by the HSPA8 gene on chromosome 11. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. Its functions contribute to biological processes including signal transduction, apoptosis, autophagy, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence, and aging.
== Structure == This gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 (Hsp70) family. As a Hsp70 protein, it has a C-terminal protein substrate-binding domain and an N-terminal ATP-binding domain. The substrate-binding domain consists of two subdomains, a two-layered β-sandwich subdomain (SBDβ) and an α-helical subdomain (SBDα), which are connected by the loop Lα,β. SBDβ contains the peptide binding pocket while SBDα serves as a lid to cover the substrate binding cleft. The ATP binding domain consists of four subdomains split into two lobes by a central ATP/ADP binding pocket. The two terminal domains are linked together by a conserved region referred to as loop LL,1, which is critical for allosteric regulation.
HSPA8, also known as heat shock cognate 71 kDa protein (HSC70), is a molecular chaperone involved in a diverse range of cellular processes. It protects the proteome from stress, assists in folding and transporting newly synthesized polypeptides, participates in chaperone-mediated autophagy, and regulates the degradation of misfolded proteins. It also plays a role in forming and dissociating protein complexes and antigen presentation. HSPA8 is a key component of the protein quality control system, ensuring proper protein folding, refolding of misfolded proteins, and controlling the targeting of proteins for degradation. This process is regulated by cycles of ATP binding, ATP hydrolysis, and ADP release, mediated by co-chaperones. These co-chaperones are categorized as J-domain co-chaperones HSP40s, nucleotide exchange factors (NEF) such as BAG1/2/3, and TPR domain chaperones like HOPX and STUB1. HSPA8's affinity for polypeptides is dependent on its nucleotide-bound state. In the ATP-bound form, it has low affinity for substrate proteins; however, upon ATP hydrolysis to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. This dynamic cycle allows for repeated substrate binding and release. HSPA8 is crucial in mitochondrial import, delivering preproteins to the TOMM70 receptor. It also acts as a repressor of transcriptional activation, inhibiting the coactivator activity of CITED1 on Smad-mediated transcription. HSPA8 is a component of the PRP19-CDC5L complex, an essential part of the spliceosome required for activating pre-mRNA splicing. It may act as a scaffold in spliceosome assembly, interacting with other core complex components. HSPA8 binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory responses, including TNF secretion by monocytes. It serves as the substrate recognition component in chaperone-mediated autophagy (CMA), a selective protein degradation pathway targeting proteins with a -KFERQ motif. HSPA8 specifically binds cytosolic proteins bearing this motif and facilitates their recruitment to the lysosomal surface, where they bind to LAMP2. These proteins are then transported into the lysosomal lumen and degraded. In conjunction with LAMP2, HSPA8 promotes MHC class II presentation of cytoplasmic antigens by guiding them to the lysosomal membrane for interaction with LAMP2, leading to MHC class II presentation of peptides on the cell membrane. HSPA8 participates in the ER-associated degradation (ERAD) quality control pathway, working with J domain-containing co-chaperones and the E3 ligase STUB1. It is recruited to clathrin-coated vesicles through its interaction with DNAJC6, leading to activation of HSPA8's ATPase activity and subsequent uncoating of these vesicles. {ECO:0000250|UniProtKB:P19120, ECO:0000269|PubMed:10722728, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:11559757, ECO:0000269|PubMed:12526792, ECO:0000269|PubMed:15894275, ECO:0000269|PubMed:21148293, ECO:0000269|PubMed:21150129, ECO:0000269|PubMed:23018488, ECO:0000269|PubMed:23990462, ECO:0000269|PubMed:24318877, ECO:0000269|PubMed:24732912, ECO:0000269|PubMed:27474739, ECO:0000269|PubMed:27916661, ECO:0000269|PubMed:2799391, ECO:0000269|PubMed:36586411, ECO:0000303|PubMed:24121476, ECO:0000303|PubMed:26865365}.
HSPA8 is also known as HEL-33, HEL-S-72p, HSC54, HSC70, HSC71, HSP71, HSP73, HSPA10, LAP-1, LAP1, NIP71.
