title: Evolution of new function through a single amino acid change in the yeast repressor Sum1p.
abstract: The SUM1-1 mutation is an example of a single amino acid change that results in new function. Wild-type Sum1p in Saccharomyces cerevisiae is a DNA-binding repressor that acts locally, whereas mutant Sum1-1p forms an extended repressive chromatin structure. By characterizing a panel of mutations in which various amino acids replaced the critical residue, threonine 988, we found that threonine was required for wild-type function and that in the absence of threonine the association of Sum1p with DNA was reduced. Isoleucine, the amino acid in mutant Sum1-1p, was required for the novel spreading property. Thus, the SUM1-1 mutation results in both a loss and a gain of function. The presence of isoleucine caused Sum1-1p to self-associate, a property that may promote spreading. In addition, isoleucine enabled Sum1-1p to associate with the origin recognition complex (ORC) and accumulate near ORC binding sites. Thus, both threonine and isoleucine at position 988 enable Sum1p to form intermolecular interactions. We propose that interaction domains may be hotspots for gain-of-function mutations because alterations in such domains have the potential to redirect a protein to new sets of binding partners. In addition, self-association of chromatin proteins may promote the formation of extended chromatin structures.
authors.affiliation: Institute for Genome Sciences and Policy, Box 3382, Duke University, Durham, NC 27710, USA.
authors.forename: Alexias
authors.initials: A
authors.lastname: Safi
authors.forename: Kelley A
authors.initials: KA
authors.lastname: Wallace
authors.forename: Laura N
authors.initials: LN
authors.lastname: Rusche
mesh_terms: D000596:Amino Acids / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D004271:DNA, Fungal / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D015966:Gene Expression Regulation, Fungal; D020868:Gene Silencing; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D018741:Replication Origin / Q000235:genetics; D012097:Repressor Proteins; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D004271:DNA, Fungal; D009687:Nuclear Proteins; D012097:Repressor Proteins; C100925:SUM1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins