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FUNCTION Mitochondrial chaperone that plays a key role in mitochondrial protein import, folding, and assembly. Plays an essential role in the protein quality control system, the correct folding of proteins, the re-folding of misfolded proteins, and the targeting of proteins for subsequent degradation. These processes are achieved through cycles of ATP binding, ATP hydrolysis, and ADP release, mediated by co-chaperones (PubMed:18632665, PubMed:25615450, PubMed:28848044, PubMed:30933555, PubMed:31177526). In mitochondria, it associates with the TIM (translocase of the inner membrane) protein complex to assist in the import and folding of mitochondrial proteins (By similarity). Plays an important role in mitochondrial iron-sulfur cluster (ISC) biogenesis, interacts with and stabilizes ISC cluster assembly proteins FXN, NFU1, NFS1 and ISCU (PubMed:26702583). Regulates erythropoiesis via stabilization of ISC assembly (PubMed:21123823, PubMed:26702583). Regulates mitochondrial calcium-dependent apoptosis by coupling two calcium channels, ITPR1 and VDAC1, at the mitochondria-associated endoplasmic reticulum (ER) membrane to facilitate calcium transport from the ER lumen to the mitochondria intermembrane space, providing calcium for the downstream calcium channel MCU, which releases it into the mitochondrial matrix (By similarity). Although primarily located in the mitochondria, it is also found in other cellular compartments. In the cytosol, it associates with proteins involved in signaling, apoptosis, or senescence. It may play a role in cell cycle regulation via its interaction with and promotion of degradation of TP53 (PubMed:24625977, PubMed:26634371). May play a role in the control of cell proliferation and cellular aging (By similarity). Protects against reactive oxygen species (ROS) (By similarity). Extracellular HSPA9 plays a cytoprotective role by preventing cell lysis following immune attack by the membrane attack complex by disrupting formation of the complex (PubMed:16091382).CATALYTIC ACTIVITY ATP + H2O = ADP + phosphate + H(+)ACTIVITY REGULATION The chaperone activity is regulated by ATP-induced allosteric coupling of the nucleotide-binding (NBD) and substrate-binding (SBD) domains. ATP binding in the NBD leads to a conformational change in the NBD, which is transferred through the interdomain linker (IDL) to the substrate-binding domain (SBD). This elicits a reduced substrate affinity and a faster substrate exchange rate. Upon hydrolysis of ATP to ADP, the protein undergoes a conformational change that increases its affinity for substrate proteins. It cycles through repeated phases of ATP hydrolysis and nucleotide exchange, facilitating repeated cycles of substrate binding and release (By similarity). Functions in collaboration with co-chaperones. Functions with the co-chaperone, DNLZ, to maintain solubility and regulate ATP hydrolysis (PubMed:18632665). Nucleotide exchange factors, GRPEL1 and GRPEL2, accelerate nucleotide exchange (PubMed:28848044).SUBUNIT Interacts strongly with the intermediate form of FXN and weakly with its mature form (PubMed:17331979, PubMed:26702583). Interacts with HSCB (PubMed:20668094). Associates with the mitochondrial contact site and cristae organizing system (MICOS) complex, composed of at least MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, APOOL/MIC27, IMMT/MIC60, APOO/MIC23/MIC26 and QIL1/MIC13. This complex was also known under the names MINOS or MitOS complex. The MICOS complex associates with mitochondrial outer membrane proteins SAMM50, MTX1, MTX2 and DNAJC11, mitochondrial inner membrane protein TMEM11 and with HSPA9 (PubMed:22114354). Interacts with DNLZ, the interaction is required to prevent self-aggregation (PubMed:23462535, PubMed:18632665). Interacts with TESPA1 (PubMed:23501103). Interacts with PDPN (PubMed:23541579). Interacts with NFU1, NFS1 and ISCU (PubMed:26702583). Interacts with TP53; the interaction promotes TP53 degradation (PubMed:24625977). Interacts (via SBD domain) with UBXN2A; the interaction with UBXN2A inhibits HSPA9 interaction with and degradation of TP53, thereby promotes TP53 translocation to the nucleus (PubMed:24625977, PubMed:26634371). Interacts with ITPR1 AND VDAC1; this interaction couples ITPR1 to VDAC1 (By similarity). Component of the TIM23 mitochondrial inner membrane pre-sequence translocase complex (PubMed:10339406).INTERACTION Found in a complex with HSPA9 and VDAC1 at the endoplasmic reticulum-mitochondria contact sites.DOMAIN The N-terminal nucleotide binding domain (NBD) is responsible for binding and hydrolyzing ATP. The C-terminal substrate-binding domain (SBD) binds to the client/substrate proteins. The two domains are allosterically coupled so that, when ATP is bound to the NBD, the SBD binds relatively weakly to clients. When ADP is bound in the NBD, a conformational change enhances the affinity of the SBD for client proteins.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.SIMILARITY Belongs to the heat shock protein 70 family.
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