3ol2 | pdb_00003ol2
Receptor-ligand structure of Human Semaphorin 4D with Plexin B1.
Structural highlights
Function[SEM4D_HUMAN] Cell surface receptor for PLXN1B and PLXNB2 that plays an important role in cell-cell signaling. Promotes reorganization of the actin cytoskeleton and plays a role in axonal growth cone guidance in the developing central nervous system. Regulates dendrite and axon branching and morphogenesis. Promotes the migration of cerebellar granule cells and of endothelial cells. Plays a role in the immune system; induces B-cells to aggregate and improves their viability (in vitro). Promotes signaling via SRC and PTK2B/PYK2, which then mediates activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Interaction with PLXNB1 mediates activation of RHOA.[1] [2] [3] [4] [PLXB1_HUMAN] Receptor for SEMA4D. Plays a role in RHOA activation and subsequent changes of the actin cytoskeleton. Plays a role in axon guidance, invasive growth and cell migration.[5] [6] [7] [8] [9] [10] Publication Abstract from PubMedCell-cell signalling of semaphorin ligands through interaction with plexin receptors is important for the homeostasis and morphogenesis of many tissues and is widely studied for its role in neural connectivity, cancer, cell migration and immune responses. SEMA4D and Sema6A exemplify two diverse vertebrate, membrane-spanning semaphorin classes (4 and 6) that are capable of direct signalling through members of the two largest plexin classes, B and A, respectively. In the absence of any structural information on the plexin ectodomain or its interaction with semaphorins the extracellular specificity and mechanism controlling plexin signalling has remained unresolved. Here we present crystal structures of cognate complexes of the semaphorin-binding regions of plexins B1 and A2 with semaphorin ectodomains (human PLXNB1(1-2)-SEMA4D(ecto) and murine PlxnA2(1-4)-Sema6A(ecto)), plus unliganded structures of PlxnA2(1-4) and Sema6A(ecto). These structures, together with biophysical and cellular assays of wild-type and mutant proteins, reveal that semaphorin dimers independently bind two plexin molecules and that signalling is critically dependent on the avidity of the resulting bivalent 2:2 complex (monomeric semaphorin binds plexin but fails to trigger signalling). In combination, our data favour a cell-cell signalling mechanism involving semaphorin-stabilized plexin dimerization, possibly followed by clustering, which is consistent with previous functional data. Furthermore, the shared generic architecture of the complexes, formed through conserved contacts of the amino-terminal seven-bladed beta-propeller (sema) domains of both semaphorin and plexin, suggests that a common mode of interaction triggers all semaphorin-plexin based signalling, while distinct insertions within or between blades of the sema domains determine binding specificity. Structural basis of semaphorin-plexin signalling.,Janssen BJ, Robinson RA, Perez-Branguli F, Bell CH, Mitchell KJ, Siebold C, Jones EY Nature. 2010 Sep 26. PMID:20877282[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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