HSP104
Domain
Has 2 AAA ATPase type nucleotide-binding domains (NBDs) per monomer, a low-affinity, high-turnover site (NBD1) and a high-affinity site (NBD2) with a 300-fold slower rate of hydrolysis. There is allosteric regulation between the 2 sites. ATP binding to NBD1 triggers binding of polypeptides and stimulates ATP hydrolysis at NBD2. Nucleotide binding to NBD2 is crucial for oligomerization.
The C-terminal extension is involved in oligomerization.
Function
Required, in concert with Hsp40 (YDJ1) and Hsp70 (SSA1) and small Hsps (HSP26), for the dissociation, resolubilization and refolding of aggregates of damaged proteins after heat or other environmental stresses. Extracts proteins from aggregates by unfolding and threading them in an ATP-dependent process through the axial channel of the protein hexamer, after which they can be refolded by components of the Hsp70/Hsp40 chaperone system. Substrate binding is ATP-dependent, and release of bound polypeptide is triggered by ATP hydrolysis. Also responsible for the maintenance of prions by dissociating prion fibrils into smaller oligomers, thereby producing transmissible seeds that can infect daughter cells during mitosis and meiosis. Loss of HSP104 can cure yeast cells of the prions [PSI+], [URE3] and [PIN+]. Excess HSP104 can also specifically cure cells of [PSI+].
Sequence Similarities
Belongs to the ClpA/ClpB family.
Cellular localization
- Cytoplasm
- Nucleus
- Shuttles between the cytoplasm and the nucleus in an importin KAP95- and KAP121-dependent and an exportin XPO1-dependent manner. Accumulation in the nucleus is enhanced by severe heat shock. In the cytoplasm, concentrates on a perivacuolar compartment, the 'insoluble protein deposit' (IPOD), in which terminally aggregated proteins are sequestered. It is also found, to a lesser extent, at a 'juxtanuclear quality control' (JUNQ) compartment, where soluble ubiquitinated misfolded proteins accumulate.
Alternative names
YLL026W, L0948, HSP104, Heat shock protein 104, Protein aggregation-remodeling factor HSP104