| Structural highlights
Function
[NRX1A_MOUSE] Cell surface protein involved in cell-cell-interactions, exocytosis of secretory granules and regulation of signal transmission. Function is isoform-specific. Alpha-type isoforms have a long N-terminus with six laminin G-like domains and play an important role in synaptic signal transmission. Alpha-type isoforms play a role in the regulation of calcium channel activity and Ca(2+)-triggered neurotransmitter release at synapses and at neuromuscular junctions. They play an important role in Ca(2+)-triggered exocytosis of secretory granules in pituitary gland. They may effect their functions at synapses and in endocrine cells via their interactions with proteins from the exocytotic machinery. Likewise, alpha-type isoforms play a role in regulating the activity of postsynaptic NMDA receptors, a subtype of glutamate-gated ion channels. Both alpha-type and beta-type isoforms may play a role in the formation or maintenance of synaptic junctions via their interactions (via the extracellular domains) with neuroligin family members, CBLN1 or CBLN2. In vitro, triggers the de novo formation of presynaptic structures. May be involved in specification of excitatory synapses. Alpha-type isoforms were first identified as receptors for alpha-latrotoxin from spider venom.[1] [2] [3] [4] [5] [6] [NXPH1_RAT] May be signaling molecules that resemble neuropeptides. Ligand for alpha-neurexins (By similarity).
Publication Abstract from PubMed
Neurexins are presynaptic, cell-adhesion molecules that specify the functional properties of synapses via interactions with trans-synaptic ligands. Neurexins are extensively alternatively spliced at six canonical sites that regulate multifarious ligand interactions, but the structural mechanisms underlying alternative splicing-dependent neurexin regulation are largely unknown. Here, we determined high-resolution structures of the complex of neurexophilin-1 and the second laminin/neurexin/sex-hormone-binding globulin domain (LNS2) of neurexin-1 and examined how alternative splicing at splice site #2 (SS2) regulates the complex. Our data reveal a unique, extensive, neurexophilin-neurexin binding interface that extends the jelly-roll beta-sandwich of LNS2 of neurexin-1 into neurexophilin-1. The SS2A insert of LNS2 augments this interface, increasing the binding affinity of LNS2 for neurexophilin-1. Taken together, our data reveal an unexpected architecture of neurexophilin-neurexin complexes that accounts for the modulation of binding by alternative splicing, which in turn regulates the competition of neurexophilin for neurexin binding with other ligands.
Structures of neurexophilin-neurexin complexes reveal a regulatory mechanism of alternative splicing.,Wilson SC, White KI, Zhou Q, Pfuetzner RA, Choi UB, Sudhof TC, Brunger AT EMBO J. 2019 Sep 30:e101603. doi: 10.15252/embj.2019101603. PMID:31566781[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Geppert M, Khvotchev M, Krasnoperov V, Goda Y, Missler M, Hammer RE, Ichtchenko K, Petrenko AG, Sudhof TC. Neurexin I alpha is a major alpha-latrotoxin receptor that cooperates in alpha-latrotoxin action. J Biol Chem. 1998 Jan 16;273(3):1705-10. PMID:9430716
- ↑ Missler M, Zhang W, Rohlmann A, Kattenstroth G, Hammer RE, Gottmann K, Sudhof TC. Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature. 2003 Jun 26;423(6943):939-48. PMID:12827191 doi:http://dx.doi.org/10.1038/nature01755
- ↑ Kattenstroth G, Tantalaki E, Sudhof TC, Gottmann K, Missler M. Postsynaptic N-methyl-D-aspartate receptor function requires alpha-neurexins. Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2607-12. PMID:14983056
- ↑ Dudanova I, Sedej S, Ahmad M, Masius H, Sargsyan V, Zhang W, Riedel D, Angenstein F, Schild D, Rupnik M, Missler M. Important contribution of alpha-neurexins to Ca2+-triggered exocytosis of secretory granules. J Neurosci. 2006 Oct 11;26(41):10599-613. PMID:17035546 doi:http://dx.doi.org/10.1523/JNEUROSCI.1913-06.2006
- ↑ Sons MS, Busche N, Strenzke N, Moser T, Ernsberger U, Mooren FC, Zhang W, Ahmad M, Steffens H, Schomburg ED, Plomp JJ, Missler M. alpha-Neurexins are required for efficient transmitter release and synaptic homeostasis at the mouse neuromuscular junction. Neuroscience. 2006;138(2):433-46. Epub 2006 Jan 10. PMID:16406382 doi:http://dx.doi.org/10.1016/j.neuroscience.2005.11.040
- ↑ Matsuda K, Yuzaki M. Cbln family proteins promote synapse formation by regulating distinct neurexin signaling pathways in various brain regions. Eur J Neurosci. 2011 Apr;33(8):1447-61. doi: 10.1111/j.1460-9568.2011.07638.x., Epub 2011 Mar 17. PMID:21410790 doi:http://dx.doi.org/10.1111/j.1460-9568.2011.07638.x
- ↑ Wilson SC, White KI, Zhou Q, Pfuetzner RA, Choi UB, Sudhof TC, Brunger AT. Structures of neurexophilin-neurexin complexes reveal a regulatory mechanism of alternative splicing. EMBO J. 2019 Sep 30:e101603. doi: 10.15252/embj.2019101603. PMID:31566781 doi:http://dx.doi.org/10.15252/embj.2019101603
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