Molecular chaperone implicated in a wide variety of cellularprocesses, including protection of the proteome from stress, foldingand transport of newly synthesized polypeptides, activation ofproteolysis of misfolded proteins and the formation and dissociation ofprotein complexes. Plays a pivotal role in the protein quality controlsystem, ensuring the correct folding of proteins, the re-folding ofmisfolded proteins and controlling the targeting of proteins forsubsequent degradation. This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. The co-chaperones have been shown to not only regulate different steps of theATPase cycle, but they also have an individual specificity such thatone co-chaperone may promote folding of a substrate while another maypromote degradation. The affinity for polypeptides is regulated by itsnucleotide bound state. In the ATP-bound form, it has a low affinityfor substrate proteins. However, upon hydrolysis of the ATP to ADP, itundergoes a conformational change that increases its affinity forsubstrate proteins. It goes through repeated cycles of ATP hydrolysisand nucleotide exchange, which permits cycles of substrate binding andrelease. The co-chaperones are of three types: J-domain co-chaperonessuch as HSP40s (stimulate ATPase hydrolysis by HSP70), the nucleotideexchange factors (NEF) such as BAG1/2/3 (facilitate conversion of HSP70from the ADP-bound to the ATP-bound state thereby promoting substraterelease), and the TPR domain chaperones such as HOPX and STUB1. Maintains proteinhomeostasis during cellular stress through two opposing mechanisms:protein refolding and degradation. Its acetylation/deacetylation statedetermines whether it functions in protein refolding or proteindegradation by controlling the competitive binding of co-chaperonesHOPX and STUB1. During the early stress response, the acetylated formbinds to HOPX which assists in chaperone-mediated protein refolding, thereafter, it is deacetylated and binds to ubiquitin ligase STUB1 thatpromotes ubiquitin-mediated protein degradation. Regulates centrosome integrity during mitosis, and is required for themaintenance of a functional mitotic centrosome that supports theassembly of a bipolar mitotic spindle. EnhancesSTUB1-mediated SMAD3 ubiquitination and degradation and facilitatesSTUB1-mediated inhibition of TGF-beta signaling. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 inregulatory T-cells (Treg) during inflammation. [1-3]

MAKAAAIGIDLGTTYSCVGVFQHGKVEIIANDQGNRTTPSYVAFTDTERLIGDAAKNQVALNPQNTVFDAKRLIGRKFGDPVVQSDMKHWPFQVINDGDKPKVQVSYKGETKAFYPEEISSMVLTKMKEIAEAYLGYPVTNAVITVPAYFNDSQRQATKDAGVIAGLNVLRIINEPTAAAIAYGLDRTGKGERNVLIFDLGGGTFDVSILTIDDGIFEVKATAGDTHLGGEDFDNRLVNHFVEEFKRKHKKDISQNKRAVRRLRTACERAKRTLSSSTQASLEIDSLFEGIDFYTSITRARFEELCSDLFRSTLEPVEKALRDAKLDKAQIHDLVLVGGSTRIPKVQKLLQDFFNGRDLNKSINPDEAVAYGAAVQAAILMGDKSENVQDLLLLDVAPLSLGLETAGGVMTALIKRNSTIPTKQTQIFTTYSDNQPGVLIQVYEGERAMTKDNNLLGRFELSGIPPAPRGVPQIEVTFDIDANGILNVTATDKSTGKANKITITNDKGRLSKEEIERMVQEAEKYKAEDEVQRERVSAKNALESYAFNMKSAVEDEGLKGKISEADKKKVLDKCQEVISWLDANTLAEKDEFEHKRKELEQVCNPIISGLYQGAGGPGPGGFGAQGPKGGSGSGPTIEEVD