title: The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D.
abstract: Semaphorins, proteins characterized by an extracellular sema domain, regulate axon guidance, immune function and angiogenesis. The crystal structure of SEMA4D (residues 1-657) shows the sema topology to be a seven-bladed beta-propeller, revealing an unexpected homology with integrins. The sema beta-propeller contains a distinctive 77-residue insertion between beta-strands C and D of blade 5. Blade 7 is followed by a domain common to plexins, semaphorins and integrins (PSI domain), which forms a compact cysteine knot abutting the side of the propeller, and an Ig-like domain. The top face of the beta-propeller presents prominent loops characteristic of semaphorins. In addition to limited contact between the Ig-like domains, the homodimer is stabilized through extensive interactions between the top faces in a sector of the beta-propeller used for heterodimerization in integrins. This face of the propeller also mediates ligand binding in integrins, and functional data for semaphorin-receptor interactions map to the equivalent surface.
authors.affiliation: Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Love
authors.forename: Karl
authors.initials: K
authors.lastname: Harlos
authors.forename: Nasim
authors.initials: N
authors.lastname: Mavaddat
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Davis
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: Robert M
authors.initials: RM
authors.lastname: Esnouf
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D039961:Semaphorins
chemical_list: D015703:Antigens, CD; C093224:CD100 antigen; D008024:Ligands; D008562:Membrane Glycoproteins; D039961:Semaphorins