PUBLICATION
Interplay of specific trans- and juxtamembrane interfaces in Plexin A3 dimerization and signal transduction
- Authors
- Barton, R., Khakbaz, P., Bera, I., Klauda, J.B., Iovine, M.K., Berger, B.W.
- ID
- ZDB-PUB-160811-6
- Date
- 2016
- Source
- Biochemistry 55(35): 4928-38 (Journal)
- Registered Authors
- Iovine, M. Kathryn
- Keywords
- none
- MeSH Terms
-
- Animals
- Dimerization
- Membrane Proteins/chemistry*
- Molecular Dynamics Simulation
- Receptors, Cell Surface/chemistry*
- Signal Transduction*
- Zebrafish/embryology
- Zebrafish Proteins/chemistry*
- PubMed
- 27508400 Full text @ Biochemistry
Citation
Barton, R., Khakbaz, P., Bera, I., Klauda, J.B., Iovine, M.K., Berger, B.W. (2016) Interplay of specific trans- and juxtamembrane interfaces in Plexin A3 dimerization and signal transduction. Biochemistry. 55(35):4928-38.
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 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. 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 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 experimental and simulation 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping