title: Structure of the semaphorin-3A receptor binding module.
abstract: The semaphorins are a large group of extracellular proteins involved in a variety of processes during development, including neuronal migration and axon guidance. Their distinctive feature is a conserved 500 amino acid semaphorin domain, a ligand-receptor interaction module also present in plexins and scatter-factor receptors. We report the crystal structure of a secreted 65 kDa form of Semaphorin-3A (Sema3A), containing the full semaphorin domain. Unexpectedly, the semaphorin fold is a variation of the beta propeller topology. Analysis of the Sema3A structure and structure-based mutagenesis data identify the neuropilin binding site and suggest a potential plexin interaction site. Based on the structure, we present a model for the initiation of semaphorin signaling and discuss potential similarities with the signaling mechanisms of other beta propeller cell surface receptors, such as integrins and the LDL receptor.
authors.affiliation: Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Antipenko
authors.forename: Juha-Pekka
authors.initials: JP
authors.lastname: Himanen
authors.forename: Klaus
authors.initials: K
authors.lastname: van Leyen
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nardi-Dei
authors.forename: Jacob
authors.initials: J
authors.lastname: Lesniak
authors.forename: William A
authors.initials: WA
authors.lastname: Barton
authors.forename: Kanagalaghatta R
authors.initials: KR
authors.lastname: Rajashankar
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Claudia
authors.initials: C
authors.lastname: Hoemme
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Püschel
authors.forename: Dimitar B
authors.initials: DB
authors.lastname: Nikolov
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D015815:Cell Adhesion Molecules / Q000378:metabolism; D051379:Mice; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D039921:Neuropilins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D040121:Semaphorin-3A / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D040681:Structural Homology, Protein
chemical_list: D015815:Cell Adhesion Molecules; D009419:Nerve Tissue Proteins; D039921:Neuropilins; D040121:Semaphorin-3A; C091529:plexin