title: The nucleotide exchange factor activity of Grp170 may explain the non-lethal phenotype of loss of Sil1 function in man and mouse.
abstract: Recent genetic work characterized homozygous mutations in the SIL1 gene as cause for the neurodegeneration that is associated with Marinesco-Sjögren syndrome in man and the woozy mouse mutant. All reported mutations were expected to result in loss of Sil1 function. Sil1 has previously been shown to act as nucleotide exchange factor for the molecular chaperone immunoglobulin heavy chain binding protein (BiP) in the lumen of the endoplasmic reticulum (ER). In the yeast ER Lhs1p was shown to be able to substitute for Sil1p and to represent an alternative nucleotide exchange activity. Therefore, by analogy the mammalian ortholog of Lhs1p, Grp170, was suggested to be able to compensate for the loss of Sil1 function in many mammalian organs. Here we characterize mammalian Grp170 as alternative nucleotide exchange factor for BiP, thus providing a likely explanation for the non-lethal phenotype of the homozygous human and murine SIL1 mutations.
authors.affiliation: Medizinische Biochemie und Molekularbiologie, Universität des Saarlandes, D-66421 Homburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weitzmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Volkmer
authors.forename: Richard
authors.initials: R
authors.lastname: Zimmermann
mesh_terms: D000818:Animals; D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C102115:LHS1 protein, S cerevisiae; D018832:Molecular Chaperones; D011506:Proteins; C418483:SIL1 protein, human; D029701:Saccharomyces cerevisiae Proteins; C050087:oxygen-regulated proteins