title: Interplay of Specific Trans- and Juxtamembrane Interfaces in Plexin A3 Dimerization and Signal Transduction.
abstract: Plexins are transmembrane proteins that serve as guidance receptors during angiogenesis, lymphangiogenesis, neuronal development, and zebrafish fin regeneration, with a putative role in cancer metastasis. Receptor dimerization or clustering, induced by extracellular ligand binding but modulated in part by the plexin transmembrane (TM) and juxtamembrane (JM) domains, is thought to drive plexin activity. Previous studies indicate that isolated plexin TM domains interact through a conserved, small-x3-small packing motif, and the cytosolic JM region interacts through a hydrophobic heptad repeat; however, the roles and interplay of these regions in plexin signal transduction remain unclear. Using an integrated experimental and simulation approach, we find disruption of the small-x3-small motifs in the Danio rerio Plexin A3 TM domain enhances dimerization of the TM-JM domain by enhancing JM-mediated dimerization. Furthermore, mutations of the cytosolic JM heptad repeat that disrupt dimerization do so even in the presence of TM domain mutations. However, mutations to the small-x3-small TM interfaces also disrupt Plexin A3 signaling in a zebrafish axonal guidance assay, indicating the importance of this TM interface in signal transduction. Collectively, our experimental and simulation results demonstrate that multiple TM and JM interfaces exist in the Plexin A3 homodimer, and these interfaces independently regulate dimerization that is important in Plexin A3 signal transduction.
authors: Department of Chemical and Biomolecular Engineering, Lehigh University , Bethlehem, Pennsylvania 18015, United States.
authors: Rachael
authors: R
authors: Barton
authors: Department of Chemical and Biomolecular Engineering, University of Maryland , College Park, Maryland 20742, United States.
authors: Pouyan
authors: P
authors: Khakbaz
authors: Department of Chemical and Biomolecular Engineering, University of Maryland , College Park, Maryland 20742, United States.
authors: Indrani
authors: I
authors: Bera
authors: Department of Chemical and Biomolecular Engineering, University of Maryland , College Park, Maryland 20742, United States.|Biophysics Program, University of Maryland , College Park, Maryland 20742-2431, United States.
authors: Jeffery B
authors: JB
authors: Klauda
authors: Department of Biological Sciences, Lehigh University , Bethlehem, Pennsylvania 18015, United States.
authors: M Kathryn
authors: MK
authors: Iovine
authors: Department of Chemical and Biomolecular Engineering, Lehigh University , Bethlehem, Pennsylvania 18015, United States.|Program in Bioengineering, Lehigh University , Bethlehem, Pennsylvania 18015, United States.
authors: Bryan W
authors: BW
authors: Berger
mesh_terms: D000818:Animals; D019281:Dimerization; D008565:Membrane Proteins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011956:Receptors, Cell Surface / Q000737:chemistry*; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000737:chemistry*
chemical_list: D008565:Membrane Proteins; C524494:Plxna3 protein, zebrafish; D011956:Receptors, Cell Surface; D029961:Zebrafish Proteins