title: Flexible nets. The roles of intrinsic disorder in protein interaction networks.
abstract: Proteins participate in complex sets of interactions that represent the mechanistic foundation for much of the physiology and function of the cell. These protein-protein interactions are organized into exquisitely complex networks. The architecture of protein-protein interaction networks was recently proposed to be scale-free, with most of the proteins having only one or two connections but with relatively fewer 'hubs' possessing tens, hundreds or more links. The high level of hub connectivity must somehow be reflected in protein structure. What structural quality of hub proteins enables them to interact with large numbers of diverse targets? One possibility would be to employ binding regions that have the ability to bind multiple, structurally diverse partners. This trait can be imparted by the incorporation of intrinsic disorder in one or both partners. To illustrate the value of such contributions, this review examines the roles of intrinsic disorder in protein network architecture. We show that there are three general ways that intrinsic disorder can contribute: First, intrinsic disorder can serve as the structural basis for hub protein promiscuity; secondly, intrinsically disordered proteins can bind to structured hub proteins; and thirdly, intrinsic disorder can provide flexible linkers between functional domains with the linkers enabling mechanisms that facilitate binding diversity. An important research direction will be to determine what fraction of protein-protein interaction in regulatory networks relies on intrinsic disorder.
authors.affiliation: Department of Biochemistry and Molecular Biology, and Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. kedunker@iupui.edu
authors.forename: A Keith
authors.initials: AK
authors.lastname: Dunker
authors.forename: Marc S
authors.initials: MS
authors.lastname: Cortese
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Lilia M
authors.initials: LM
authors.lastname: Iakoucheva
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
mesh_terms: D000818:Animals; D001665:Binding Sites; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism; D002468:Cell Physiological Phenomena; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D024003:HMGA Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D051760:Xeroderma Pigmentosum Group A Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: D002147:Calmodulin; D024003:HMGA Proteins; D011506:Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D000071679:Glycogen Synthase Kinase 3 beta; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3