title: Disulfide bond acquisition through eukaryotic protein evolution.
abstract: Disulfide bonds play critical roles in protein stability and function. They are generally considered to be strongly conserved among species. Although there is compelling evidence in the literature for this conservation on a case-by-case basis, comparative genomic analyses of disulfide conservation have in the past been limited. By analyzing the conservation of all structurally validated disulfide bonds from the Protein Data Bank across 29 completely sequenced eukaryotic genomes, we observe elevated conservation of disulfide-bonded cysteines (half-cystines) compared with unpaired cysteines and other amino acids. Remarkably, half-cystines are even more conserved than tryptophan--the most conserved amino acid. Overall, once disulfide bonds are acquired in proteins, they are rarely lost. Moreover, the acquisition of disulfide bonds shows a strong positive correlation (R(2) = 0.74) with organismal complexity. Although the correlation weakens (R(2) = 0.59) when yeast is excluded from the analysis, this trend is still apparent when compared with the slightly negative correlation of unpaired cysteine acquisition with organismal complexity. The accrual of disulfide bonds is likely to reflect the demand for greater sophistication in protein function in complex species. Our findings provide further support for the increasing usage of cysteines in modern proteomes and suggest that there has been positive selection for disulfide bonds through eukaryotic evolution. Finally, we show that the acquisition of the functionally relevant disulfide bond in domain 2 of the CD4 protein occurred independently in primates and rodents.
authors.affiliation: Prince of Wales Clinical School and Lowy Cancer Research Centre, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Jason W H
authors.initials: JW
authors.lastname: Wong
authors.forename: Simon Y W
authors.initials: SY
authors.lastname: Ho
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hogg
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D003553:Cystine / Q000737:chemistry / Q000235:genetics; D030541:Databases, Genetic; D004220:Disulfides / Q000737:chemistry*; D056890:Eukaryota; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D002679:Pan troglodytes / Q000235:genetics; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D004220:Disulfides; D011506:Proteins; D003553:Cystine