title: Bringing order to protein disorder through comparative genomics and genetic interactions.
abstract: BACKGROUND
  Intrinsically disordered regions are widespread, especially in proteomes of higher eukaryotes. Recently, protein disorder has been associated with a wide variety of cellular processes and has been implicated in several human diseases. Despite its apparent functional importance, the sheer range of different roles played by protein disorder often makes its exact contribution difficult to interpret.
  
  
  RESULTS
  We attempt to better understand the different roles of disorder using a novel analysis that leverages both comparative genomics and genetic interactions. Strikingly, we find that disorder can be partitioned into three biologically distinct phenomena: regions where disorder is conserved but with quickly evolving amino acid sequences (flexible disorder); regions of conserved disorder with also highly conserved amino acid sequences (constrained disorder); and, lastly, non-conserved disorder. Flexible disorder bears many of the characteristics commonly attributed to disorder and is associated with signaling pathways and multi-functionality. Conversely, constrained disorder has markedly different functional attributes and is involved in RNA binding and protein chaperones. Finally, non-conserved disorder lacks clear functional hallmarks based on our analysis.
  
  
  CONCLUSIONS
  Our new perspective on protein disorder clarifies a variety of previous results by putting them into a systematic framework. Moreover, the clear and distinct functional association of flexible and constrained disorder will allow for new approaches and more specific algorithms for disorder detection in a functional context. Finally, in flexible disordered regions, we demonstrate clear evolutionary selection of protein disorder with little selection on primary structure, which has important implications for sequence-based studies of protein structure and evolution.
authors.affiliation: Department of Computer Science and Engineering, University of Minnesota, 200 Union Street SE, Minneapolis, MN 55455, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bellay
authors.forename: Sangjo
authors.initials: S
authors.lastname: Han
authors.forename: Magali
authors.initials: M
authors.lastname: Michaut
authors.forename: Taehyung
authors.initials: T
authors.lastname: Kim
authors.forename: Michael
authors.initials: M
authors.lastname: Costanzo
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Andrews
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.forename: Chad L
authors.initials: CL
authors.lastname: Myers
authors.forename: Philip M
authors.initials: PM
authors.lastname: Kim
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D030562:Databases, Protein; D004926:Escherichia coli; D019143:Evolution, Molecular; D023281:Genomics / Q000379:methods*; D006801:Humans; D015233:Models, Statistical; D008969:Molecular Sequence Data; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000235:genetics*; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D059467:Transcriptome
chemical_list: D011506:Proteins