title: Evolution of oligomeric state through allosteric pathways that mimic ligand binding.
abstract: Evolution and design of protein complexes are almost always viewed through the lens of amino acid mutations at protein interfaces. We showed previously that residues not involved in the physical interaction between proteins make important contributions to oligomerization by acting indirectly or allosterically. In this work, we sought to investigate the mechanism by which allosteric mutations act, using the example of the PyrR family of pyrimidine operon attenuators. In this family, a perfectly sequence-conserved helix that forms a tetrameric interface is exposed as solvent-accessible surface in dimeric orthologs. This means that mutations must be acting from a distance to destabilize the interface. We identified 11 key mutations controlling oligomeric state, all distant from the interfaces and outside ligand-binding pockets. Finally, we show that the key mutations introduce conformational changes equivalent to the conformational shift between the free versus nucleotide-bound conformations of the proteins.
authors.affiliation: European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Medical Research Council (MRC) Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Tina
authors.initials: T
authors.lastname: Perica
authors.affiliation: Medical Research Council (MRC) Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Department of Molecular Biology, University of Bergen University of Bergen, P.O. Box 7803, N-5020 Bergen, Norway. Computational Biology Unit, Department of Informatics, University of Bergen, P.O. Box 7803, N-5020 Bergen, Norway.
authors.forename: Sandhya P
authors.initials: SP
authors.lastname: Tiwari
authors.affiliation: Medical Research Council (MRC) Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: McLaughlin
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Kemplen
authors.affiliation: European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Xiuwei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Annette
authors.initials: A
authors.lastname: Steward
authors.affiliation: Department of Molecular Biology, University of Bergen University of Bergen, P.O. Box 7803, N-5020 Bergen, Norway. Computational Biology Unit, Department of Informatics, University of Bergen, P.O. Box 7803, N-5020 Bergen, Norway.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Reuter
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Clarke
authors.affiliation: European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. saraht@ebi.ac.uk.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Teichmann
mesh_terms: D000494:Allosteric Regulation / Q000235:genetics*; D000595:Amino Acid Sequence; D001412:Bacillus subtilis / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics; D017124:Conserved Sequence; D019143:Evolution, Molecular; D008024:Ligands; D009154:Mutation; D010430:Pentosyltransferases / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D015202:Protein Engineering; D055503:Protein Multimerization / Q000235:genetics*; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D008024:Ligands; D012097:Repressor Proteins; D010430:Pentosyltransferases; C098851:PyrR protein, bacteria