title: The guanine nucleotide exchange factor Rlf interacts with SH3 domain-containing proteins via a binding site with a preselected conformation.
abstract: Rlf is a guanine nucleotide exchange factor for the small G-proteins RalA and RalB and couples Ras- to Ral-signalling. Here the crystal structure of the catalytic module of Rlf consisting of a REM- and a CDC25-homology domain is determined. The structure is distinguished by an extended three stranded β-sheet called the flagpole. The flagpole is a conserved element in the RalGDS family of guanine nucleotide exchange factors and stabilises the orientation of the REM-domain relative to the CDC25-homology domain. A proline-rich sequence in the flagpole is unique to Rlf and several proteins that interact with this sequence by SH3 domains are identified. Conformational pre-selection results in a gain of affinity and contributes to the establishment of SH3 domain selectivity.
authors.affiliation: Department of Molecular Cancer Research, Centre of Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Milica
authors.initials: M
authors.lastname: Popovic
authors.affiliation: Department of Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, The Netherlands.
authors.forename: Arjen J
authors.initials: AJ
authors.lastname: Jakobi
authors.affiliation: Department of Molecular Cancer Research, Centre of Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Rensen-de Leeuw
authors.affiliation: Department of Molecular Cancer Research, Centre of Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: h.rehmann@umcutrecht.nl.
authors.forename: Holger
authors.initials: H
authors.lastname: Rehmann
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D024461:Myosin Type I / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry; D051966:Phospholipase C gamma / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D014157:Transcription Factors / Q000737:chemistry*; D018909:src Homology Domains
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D020662:Guanine Nucleotide Exchange Factors; C509776:ITSN2 protein, human; D010446:Peptide Fragments; C490805:Rgl2 protein, mouse; D014157:Transcription Factors; C522157:PLCG1 protein, human; D051966:Phospholipase C gamma; C511011:MYO1E protein, human; D024461:Myosin Type I
keywords: Crystal structure; Guanine nucleotide exchange factor; Pre-selected binding conformation; Rlf/Rgl2; SH3 domain; Small G-protein