SUMMARY PARAGRAPH for SSA1
SSA1, SSA2, SSA3, and SSA4 encode chaperone proteins that comprise the S. cerevisiae SSA subfamily of cytosolic HSP70 proteins (10). 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 11 and 12). 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 (13, 14, 15, 16, and reviewed in 17, 12, and 11). 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 Ssa1p sharing 99%, 84%, and 85% amino acid identity with Ssa2p, Ssa3p, and Ssa4p, respectively (18). Although SSA1 basal expression is significant under normal growth conditions, transcription is also upregulated before diauxic shift or upon heat shock (19, 20). Increased expression after heat shock is mediated by the transcriptional activator Hsf1p, which recognizes and binds two heat shock elements (HSE) in the SSA1 promoter (21). Of the two HSEs, only one contributes to basal expression (22). Although the majority of Ssa protein is found in the cytosol, Ssa1p and Ssa2p can also be detected in the cell wall (3). Additionally, Ssa1p and Ssa2p have been implicated in DNA-damage as they have been identified as members of Rad9 DNA-checkpoint complexes (23, 24).
Most of the structural knowledge of the S. cerevisiae HSP70 proteins is based on experimental evidence from bacterial DnaK, mammalian HSP70, and Ssa1p (25 and reviewed in 11). 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 11). 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 (26, 27, 28, 29). 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 11). The rate of Ssa protein ATP/ADP exchange is stimulated by the nucleotide exchange factors Fes1p and Snl1p (30, 31).
The effect of SSA1 expression has also been studied in yeast models of human prion disease such as Creutzfeldt-Jakob disease (OMIM). For the [PSI+] prion (an isoform of Sup35p), overexpression of any one of the Ssa proteins promotes prion formation and suppresses the ability of Hsp104p to cure prion propagation (32 and reviewed in 33). In contrast, overexpression of SSA1 is able to cure cells infected with the yeast prion [URE3] (an isoform of Ure2p) (34). In cells carrying the [PIN+] prion (an isoform of Rnq1p), ssa1ssa2 double null mutations result in the loss of polyglutamine aggregate expansion and toxicity, which are two hallmarks of Huntington disease (OMIM) (35).
Last updated: 2006-02-06