| Structural highlights
Function
PLXB1_HUMAN Receptor for SEMA4D. Plays a role in RHOA activation and subsequent changes of the actin cytoskeleton. Plays a role in axon guidance, invasive growth and cell migration.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Plexin-B1 is a receptor for the cell surface semaphorin, Sema4D. This signalling system has been implicated in a variety of human diseases, including cancer, multiple sclerosis and osteoporosis. Whilst inhibitors of the Plexin-B1:Sema4D interaction have been previously reported, understanding their mechanism has been hindered by an incomplete structural view of Plexin-B1. In this study, we have raised and characterised a pair of nanobodies that are specific for mouse Plexin-B1, and which inhibit the binding of Sema4D to mouse Plexin-B1 and its biological activity. Structural studies of these nanobodies reveal that they inhibit the binding of Sema4D in an allosteric manner, binding to epitopes not previously reported. In addition, we report the first unbound structure of human Plexin-B1, which reveals that Plexin-B1 undergoes a conformational change on Sema4D binding. These changes mirror those seen upon binding of allosteric peptide modulators, which suggests a new model for understanding Plexin-B1 signalling, and provides a potential innovative route for therapeutic modulation of Plexin-B1.
Nanobody inhibitors of Plexin-B1 identify allostery in plexin-semaphorin interactions and signalling.,Cowan R, Trokter M, Oleksy A, Fedorova M, Sawmynaden K, Worzfeld T, Offermanns S, Matthews D, Carr MD, Hall G J Biol Chem. 2023 Apr 21:104740. doi: 10.1016/j.jbc.2023.104740. PMID:37088134[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, Tamagnone L, Comoglio PM. The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol. 2002 Sep;4(9):720-4. PMID:12198496 doi:10.1038/ncb843
- ↑ Aurandt J, Vikis HG, Gutkind JS, Ahn N, Guan KL. The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12085-90. Epub 2002 Aug 26. PMID:12196628 doi:10.1073/pnas.142433199
- ↑ Swiercz JM, Kuner R, Offermanns S. Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol. 2004 Jun 21;165(6):869-80. PMID:15210733 doi:10.1083/jcb.200312094
- ↑ Tong Y, Hota PK, Penachioni JY, Hamaneh MB, Kim S, Alviani RS, Shen L, He H, Tempel W, Tamagnone L, Park HW, Buck M. Structure and function of the intracellular region of the plexin-b1 transmembrane receptor. J Biol Chem. 2009 Dec 18;284(51):35962-72. Epub . PMID:19843518 doi:10.1074/jbc.M109.056275
- ↑ Janssen BJ, Robinson RA, Perez-Branguli F, Bell CH, Mitchell KJ, Siebold C, Jones EY. Structural basis of semaphorin-plexin signalling. Nature. 2010 Sep 26. PMID:20877282 doi:10.1038/nature09468
- ↑ Bell CH, Aricescu AR, Jones EY, Siebold C. A Dual Binding Mode for RhoGTPases in Plexin Signalling. PLoS Biol. 2011 Aug;9(8):e1001134. Epub 2011 Aug 30. PMID:21912513 doi:10.1371/journal.pbio.1001134
- ↑ Cowan R, Trokter M, Oleksy A, Fedorova M, Sawmynaden K, Worzfeld T, Offermanns S, Matthews D, Carr MD, Hall G. Nanobody inhibitors of Plexin-B1 identify allostery in plexin-semaphorin interactions and signalling. J Biol Chem. 2023 Apr 21:104740. PMID:37088134 doi:10.1016/j.jbc.2023.104740
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