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The neuronal protein Neurexin directly interacts with the Scribble-Pix complex to stimulate F-actin assembly for synaptic vesicle clustering.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2017 Sep 01; Vol. 292 (35), pp. 14334-14348. Date of Electronic Publication: 2017 Jul 14. - Publication Year :
- 2017
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Abstract
- Synaptic vesicles (SVs) form distinct pools at synaptic terminals, and this well-regulated separation is necessary for normal neurotransmission. However, how the SV cluster, in particular synaptic compartments, maintains normal neurotransmitter release remains a mystery. The presynaptic protein Neurexin (NRX) plays a significant role in synaptic architecture and function, and some evidence suggests that NRX is associated with neurological disorders, including autism spectrum disorders. However, the role of NRX in SV clustering is unclear. Here, using the neuromuscular junction at the 2-3 instar stages of Drosophila larvae as a model and biochemical imaging and electrophysiology techniques, we demonstrate that Drosophila NRX (DNRX) plays critical roles in regulating synaptic terminal clustering and release of SVs. We found that DNRX controls the terminal clustering and release of SVs by stimulating presynaptic F-actin. Furthermore, our results indicate that DNRX functions through the scaffold protein Scribble and the GEF protein DPix to activate the small GTPase Ras-related C3 Botulinum toxin substrate 1 (Rac1). We observed a direct interaction between the C-terminal PDZ-binding motif of DNRX and the PDZ domains of Scribble and that Scribble bridges DNRX to DPix, forming a DNRX-Scribble-DPix complex that activates Rac1 and subsequently stimulates presynaptic F-actin assembly and SV clustering. Taken together, our work provides important insights into the function of DNRX in regulating SV clustering, which could help inform further research into pathological neurexin -mediated mechanisms in neurological disorders such as autism.<br /> (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- ATP-Binding Cassette Transporters chemistry
ATP-Binding Cassette Transporters genetics
Animals
Animals, Genetically Modified
Cell Adhesion Molecules, Neuronal chemistry
Cell Adhesion Molecules, Neuronal genetics
Drosophila Proteins agonists
Drosophila Proteins chemistry
Drosophila Proteins genetics
Drosophila melanogaster cytology
Drosophila melanogaster genetics
Drosophila melanogaster growth & development
Electrophysiological Phenomena
Gene Deletion
Green Fluorescent Proteins genetics
Green Fluorescent Proteins metabolism
HEK293 Cells
Humans
Larva cytology
Larva genetics
Larva growth & development
Larva metabolism
Membrane Proteins chemistry
Membrane Proteins genetics
Mutation
Nerve Tissue Proteins chemistry
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Neuromuscular Junction cytology
Neuromuscular Junction growth & development
Peptide Fragments chemistry
Peptide Fragments genetics
Peptide Fragments metabolism
Protein Interaction Domains and Motifs
Protein Multimerization
Recombinant Fusion Proteins chemistry
Recombinant Fusion Proteins metabolism
rac GTP-Binding Proteins agonists
rac GTP-Binding Proteins chemistry
rac GTP-Binding Proteins metabolism
ATP-Binding Cassette Transporters metabolism
Actin Cytoskeleton metabolism
Cell Adhesion Molecules, Neuronal metabolism
Drosophila Proteins metabolism
Drosophila melanogaster metabolism
Membrane Proteins metabolism
Neuromuscular Junction metabolism
Synaptic Vesicles metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 292
- Issue :
- 35
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28710284
- Full Text :
- https://doi.org/10.1074/jbc.M117.794040