HSPA1A
Description
The HSPA1A (heat shock protein family A (Hsp70) member 1A) is a protein-coding gene located on chromosome 6.
Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the HSPA1A gene. 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. In addition, Hsp72 also facilitates DNA repair. Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and inflammatory diseases such as Diabetes mellitus type 2 and rheumatoid arthritis.
== Structure == This intronless 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.
HSPA1A, also known as Heat shock 70 kDa protein 1, is a molecular chaperone involved in a wide array of cellular processes, including protecting the proteome from stress, folding and transporting newly synthesized polypeptides, activating the proteolysis of misfolded proteins, and forming and dissociating protein complexes. It plays a crucial role in the protein quality control system, ensuring the proper folding of proteins, re-folding of misfolded proteins, and controlling the targeting of proteins for subsequent degradation. This is achieved through cycles of ATP binding, ATP hydrolysis, and ADP release, mediated by co-chaperones. These co-chaperones regulate different steps in the ATPase cycle and have individual specificity, meaning one co-chaperone may promote folding of a substrate while another may promote degradation. The affinity for polypeptides is regulated by its nucleotide bound state. In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. It goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release. There are three types of co-chaperones: J-domain co-chaperones such as HSP40s (stimulate ATPase hydrolysis by HSP70), nucleotide exchange factors (NEF) such as BAG1/2/3 (facilitate conversion of HSP70 from the ADP-bound to the ATP-bound state, promoting substrate release), and TPR domain chaperones such as HOPX and STUB1. HSPA1A maintains protein homeostasis during cellular stress through two opposing mechanisms: protein refolding and degradation. Its acetylation/deacetylation state determines whether it functions in protein refolding or protein degradation by controlling the competitive binding of co-chaperones HOPX and STUB1. During the early stress response, the acetylated form binds to HOPX, assisting in chaperone-mediated protein refolding. Thereafter, it is deacetylated and binds to ubiquitin ligase STUB1, which promotes ubiquitin-mediated protein degradation. HSPA1A regulates centrosome integrity during mitosis and is required for the maintenance of a functional mitotic centrosome that supports the assembly of a bipolar mitotic spindle. It enhances STUB1-mediated SMAD3 ubiquitination and degradation and facilitates STUB1-mediated inhibition of TGF-beta signaling. It is essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation. HSPA1A is required as a co-chaperone for optimal STUB1/CHIP ubiquitination of NFATC3. It negatively regulates heat shock-induced HSF1 transcriptional activity during the attenuation and recovery phase period of the heat shock response. HSPA1A is involved in the clearance of misfolded PRDM1/Blimp-1 proteins by sequestering them in the cytoplasm and promoting their association with SYNV1/HRD1, leading to proteasomal degradation.
HSPA1A is also known as HEL-S-103, HSP70, HSP70-1, HSP70-1A, HSP70-2, HSP70.1, HSP70.2, HSP70I, HSP72, HSPA1.
