SUMMARY PARAGRAPH for SSA3
SSA1, SSA2, SSA3, and SSA4 encode chaperone proteins that comprise the S. cerevisiae SSA subfamily of cytosolic HSP70 proteins (1). HSP70 is a large family of proteins that has been evolutionarily conserved from bacteria (DnaK) to humans (HSP72/73). HSP70 proteins were originally classified based upon their induction by heat shock and their size of ~70kDa. The main function of these proteins is to serve as molecular chaperones, binding newly-translated proteins to assist in proper folding and prevent aggregation/misfolding (reviewed in 5 and 6). In yeast, HSP70s are also involved in disassembling aggregates of misfolded proteins, translocating select proteins into the mitochondria and ER, degrading aberrant proteins, and regulating the expression of other heat shock proteins (7, 8, 9, 10, and reviewed in 11, 6, and 5). S. cerevisiae has at least 9 cytosolic forms of HSP70 (SSA1, SSA2, SSA3, SSA4, SSB1, SSB2, SSE1, SSE2, SSZ1), 2 HSP70s which are found in the endoplasmic reticulum (KAR2, LHS1), and 3 mitochondrial HSP70s (SSC1, SSQ1, ECM10).
The 4 genes of the SSA subfamily are closely related, with Ssa3p sharing 84% amino acid identity with Ssa1p and Ssa2p and 90% identity with Ssa4p (12). SSA3 expression is not detectable under normal growth conditions but is induced after the diauxic shift or upon heat shock (13, 1). Increased expression after heat shock is mediated by the transcriptional activator Hsf1p, which recognizes and binds to a heat shock element in the SSA3 promoter (14, 15). An SSA3 null mutant is viable and has no detectable phenotype. In an ssa1ssa2ssa4 triple null mutant, endogenous levels of Ssa3p are not enough to sustain viability, but expression of the SSA3 gene from the endogenous SSA2 promoter is able to rescue the cells (1).
Most of the structural knowledge of the S. cerevisiae HSP70 proteins is based on experimental evidence from bacterial DnaK, mammalian HSP70, and Ssa1p (16 and reviewed in 5). All Hsp70s contain an N-terminal ATPase domain and a C-terminal peptide binding domain. ATPase activity of HSP70s is intrinsically weak but can be enhanced by interaction with DnaJ/HSP40 proteins (reviewed in 5). It has been shown for Ssa1p, and based on similarity is implicated for the remaining Ssa subfamily, that activity is stimulated by interaction with the DnaJ/HSP40 co-chaperones Ydj1p, Sis1p, Sti1p, and Cns1p (2, 17, 18, 19). Substrate binding is regulated by ATP turnover; in the presence of ATP, peptide exchange is rapid and the binding constant is low while when ADP is bound, peptide exchange is slower and the substrate affinity higher (reviewed in 5). The rate of Ssa protein ATP/ADP exchange is stimulated by the nucleotide exchange factors Fes1p and Snl1p (20, 21).
The effect of SSA3 expression has also been studied in yeast models of human disease, such as the prion disease Creutzfeldt-Jakob disease (OMIM) and Parkinson disease (OMIM). Overexpression of any of the SSA gene products promotes the formation of the [PSI+] prion (an isoform of Sup35p) and suppresses the ability of Hsp104p to cure prion propagation (22 and reviewed in 23). However, overexpression of Ssa3p has been shown to protect S. cerevisiae cells that express the human alpha-synuclein, the protein that forms amyloid fibers in Parkinson disease, from apoptosis (24).
Last updated: 2006-02-06