Disease relevance of SIS1

• A conditional ydj1 mutant strain (ydj1-151TS) is defective for import of several polypeptides into mitochondria and alpha factor into the endoplasmic reticulum at 37 degrees C. These defects are suppressed by E. coli dnaJ or overexpression of S. cerevisiae SIS1 proteins [1].

High impact information on SIS1

• Hsp82p, Ssa1p and Sis1p, individually, do not affect assembly [2].
• Our data indicated that deficiencies in molecular chaperones Sis1 and Hsp104 inhibited seeding of polyQ aggregates, whereas ssa1, ssa2, and ydj1-151 mutations inhibited expansion of aggregates [3].
• Using a prion chimera we demonstrate that the prion-determinant domain of Rnq1 is genetically sufficient for control by Sis1 [4].
• However, the biological importance of this model is challenged by the fact that deletion of the substrate-binding domain of either of the two major Hsp40s of the yeast cytosol, Ydj1 and Sis1, leads to no severe defects, as long as regions necessary for Hsp70 interaction are retained [5].
• However, only three amino acid changes in the Sis1p J domain render the Sec63 fusion protein fully functional in the ER lumen [6].

Biological context of SIS1

• The Saccharomyces cerevisiae SIS1 gene was identified as a high copy number suppressor of the slow growth phenotype of strains containing mutations in the SIT4 gene, which encodes a predicted serine/threonine protein phosphatase [7].
• The autoregulation of SIS1 transcription is mediated through a 39-base pair cis-element containing the SIS1 heat shock element plus additional flanking sequences on one side [8].
• Nucleotide sequence comparison results in relocation of the SIS1 gene to the left arm of the chromosome as confirmed by colinearity analysis [9].
• Using a plant DnaJ probe and a cDNA library constructed from poly(A)(+)-RNA of A. curvatum grown on oleate we isolated a SIS1 cDNA coding for a 39.5 kDa protein [10].
• Purified SYS and YSY exhibited protein-folding activity and substrate specificity that mimicked that of Ydj1 and Sis1, respectively [11].

Anatomical context of SIS1

• Sis1 is an essential Hsp40 of the cytosol of Saccharomyces cerevisiae, thought to be required for initiation of translation [12].
• The yeast hsp70 homologue Ssa is required for translation and interacts with Sis1 and Pab1 on translating ribosomes [13].
• Strains limited for the SIS1 protein accumulate cells that appear blocked for migration of the nucleus from the mother cell into the daughter cell [7].
• In addition, sucrose gradient sedimentation analysis of polysomes from T. cruzi and a yeast mutant overexpressing TcJ6p showed that the trypanosomal co-chaperone was closely associated with ribosomal subunits, 80 S monosomes and the smaller polysomes, as observed for Sis1p [14].

Associations of SIS1 with chemical compounds

• This region of SIS1 contains a glycine/methionine-rich region which, along with more amino-terminal sequences, is required for SIS1 to associate with a protein of apparent molecular mass of 40 kD [7].
• However, there is some functional redundancy within the glycine-rich regions of Sis1, because a deletion of the adjacent glycine/methionine (G/M) region was somewhat defective in propagation of [RNQ(+)] as well [15].
• An extended glycine-rich region of Sis1, composed of a region rich in phenylalanine residues (G/F) and another rich in methionine residues (G/M), is critical for prion maintenance [15].

Other interactions of SIS1

• We further show that a related yeast protein, SIS1, is a multicopy suppressor of YDJ1 [16].
• Consistent with a function in translation, depletion of Ssa protein produces a general translational defect that appears similar to loss of Sis1 and Pab1 function [13].
• A specific Sis1 deletion mutant altered the physical aggregation pattern of Rnq1 without curing the prion [4].

Analytical, diagnostic and therapeutic context of SIS1

• Atomic force microscopy of the Sis1-Ssa1 complex showed that only one end of the Ssa1 lid domain binds the Sis1 peptide-binding-fragment dimer at the upper level of the huge groove within the Sis1 dimer [17].

References