419738 Interplay of Specific Trans- and Juxtamembrane Interfaces in the Regulation of Plexin-Semaphorin Signaling

Wednesday, November 11, 2015
Exhibit Hall 1 (Salt Palace Convention Center)
Bryan W. Berger1, Rachael Barton1 and M. Kathryn Iovine2, (1)Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA, (2)Biological Sciences, Lehigh University, Bethlehem, PA

Plexins are type I integral membrane 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 through 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, but the roles and interplay of these regions in plexin signal transduction remains unclear.  In this study, we find disruption of the small-x3-small motifs in the Danio rerioplexin A3 TM domain enhances dimerization of the TM-JM domain in the AraTM assay by enhancing JM-mediated dimerization, whereas mutations to 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 results demonstrate that multiple TM and JM interfaces exist in the plexin A3 homodimer, and these interfaces independently regulate dimerization important in plexin A3 signal transduction. Furthermore, this work highlights the importance of JM interactions as well as how the interplay of TM and JM interactions can independently regulate receptor signal transduction.

This work was supported by the National Science Foundation (CBET-1227924) and the National Institutes of Health (P01 HL040387-26A1).

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