title: The intrinsically disordered regions of the Drosophila melanogaster Hox protein ultrabithorax select interacting proteins based on partner topology.
abstract: Interactions between structured proteins require a complementary topology and surface chemistry to form sufficient contacts for stable binding. However, approximately one third of protein interactions are estimated to involve intrinsically disordered regions of proteins. The dynamic nature of disordered regions before and, in some cases, after binding calls into question the role of partner topology in forming protein interactions. To understand how intrinsically disordered proteins identify the correct interacting partner proteins, we evaluated interactions formed by the Drosophila melanogaster Hox transcription factor Ultrabithorax (Ubx), which contains both structured and disordered regions. Ubx binding proteins are enriched in specific folds: 23 of its 39 partners include one of 7 folds, out of the 1195 folds recognized by SCOP. For the proteins harboring the two most populated folds, DNA-RNA binding 3-helical bundles and α-α superhelices, the regions of the partner proteins that exhibit these preferred folds are sufficient for Ubx binding. Three disorder-containing regions in Ubx are required to bind these partners. These regions are either alternatively spliced or multiply phosphorylated, providing a mechanism for cellular processes to regulate Ubx-partner interactions. Indeed, partner topology correlates with the ability of individual partner proteins to bind Ubx spliceoforms. Partners bind different disordered regions within Ubx to varying extents, creating the potential for competition between partners and cooperative binding by partners. The ability of partners to bind regions of Ubx that activate transcription and regulate DNA binding provides a mechanism for partners to modulate transcription regulation by Ubx, and suggests that one role of disorder in Ubx is to coordinate multiple molecular functions in response to tissue-specific cues.
authors.affiliation: Reynolds Medical Building, Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, Texas, United States of America.
authors.forename: Hao-Ching
authors.initials: HC
authors.lastname: Hsiao
authors.affiliation: Reynolds Medical Building, Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, Texas, United States of America.
authors.forename: Kim L
authors.initials: KL
authors.lastname: Gonzalez
authors.affiliation: Department of Biochemistry and Cell Biology, Rice University, Houston, Texas, United States of America.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Catanese
authors.affiliation: Department of Biochemistry and Cell Biology, Rice University, Houston, Texas, United States of America.
authors.forename: Kristopher E
authors.initials: KE
authors.lastname: Jordy
authors.affiliation: Department of Biochemistry and Cell Biology, Rice University, Houston, Texas, United States of America.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Matthews
authors.affiliation: Reynolds Medical Building, Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, Texas, United States of America; Department of Biochemistry and Cell Biology, Rice University, Houston, Texas, United States of America.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bondos
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism*; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020543:Proteome / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D064267:Intrinsically Disordered Proteins; D050505:Mutant Proteins; D020033:Protein Isoforms; D020543:Proteome; D014157:Transcription Factors; C066177:Ubx protein, Drosophila; D004247:DNA