plexin

All plexins have an extracellular SEMA domain at their N-terminus. This is a structural motif common among all semaphorins and plexins and is responsible for this binding of semaphorin dimers, which are the native conformation for these ligands in vivo.{{cite journal | vauthors = Pascoe HG, Wang Y, Zhang X | title = Structural mechanisms of plexin signaling | journal = Progress in Biophysics and Molecular Biology | volume = 118 | issue = 3 | pages = 161–8 | date = September 2015 | pmid = 25824683 | pmc = 4537802 | doi = 10.1016/j.pbiomolbio.2015.03.006 }} This is followed by alternating plexin, semaphorin, and integrin (PSI) domains and immunoglobulin-like, plexin, and transcription factors (IPT) domains.{{cite journal | vauthors = Suzuki K, Tsunoda H, Omiya R, Matoba K, Baba T, Suzuki S, Segawa H, Kumanogoh A, Iwasaki K, Hattori K, Takagi J | title = Structure of the Plexin Ectodomain Bound by Semaphorin-Mimicking Antibodies | journal = PLOS ONE | volume = 11 | issue = 6 | pages = e0156719 | date = June 2016 | pmid = 27258772 | pmc = 4892512 | doi = 10.1371/journal.pone.0156719 | bibcode = 2016PLoSO..1156719S | doi-access = free }} Each of these is named for the proteins in which their structure is conserved.{{cite journal | vauthors = Messina A, Giacobini P | title = Semaphorin signaling in the development and function of the gonadotropin hormone-releasing hormone system | journal = Frontiers in Endocrinology | volume = 4 | pages = 133 | date = September 2013 | pmid = 24065959 | pmc = 3779810 | doi = 10.3389/fendo.2013.00133 | doi-access = free }}{{cite journal | vauthors = Kozlov G, Perreault A, Schrag JD, Park M, Cygler M, Gehring K, Ekiel I | title = Insights into function of PSI domains from structure of the Met receptor PSI domain | journal = Biochemical and Biophysical Research Communications | volume = 321 | issue = 1 | pages = 234–40 | date = August 2004 | pmid = 15358240 | doi = 10.1016/j.bbrc.2004.06.132 }} Collectively, the extracellular region resembles a curved stalk projecting in a clockwise direction.

Before bindings its semaphorin dimer ligand, associations between the extracellular domains of pre-formed plexin dimers keeps their intracellular domains segregated and inactive.{{cite journal | vauthors = Takahashi T, Strittmatter SM | title = Plexina1 autoinhibition by the plexin sema domain | journal = Neuron | volume = 29 | issue = 2 | pages = 429–39 | date = February 2001 | pmid = 11239433 | doi = 10.1016/S0896-6273(01)00216-1 | doi-access = free }}{{cite journal | vauthors = Marita M, Wang Y, Kaliszewski MJ, Skinner KC, Comar WD, Shi X, Dasari P, Zhang X, Smith AW | title = Class A Plexins Are Organized as Preformed Inactive Dimers on the Cell Surface | journal = Biophysical Journal | volume = 109 | issue = 9 | pages = 1937–45 | date = November 2015 | pmid = 26536270 | pmc = 4643210 | doi = 10.1016/j.bpj.2015.04.043 | bibcode = 2015BpJ...109.1937M }} This allows for co-localization of plexin dimers to be primed for binding of semaphorin dimers and activation of intracellular machinery.

Highly conserved intracellular domains consisting of a bipartite segment which functions as a GTPase-Activating Protein (GAP). Plexin is the only known receptor molecule to have a GAP domain. In the inactive state, these two sections are separated by a Rho-GTPase binding domain (RBD). When the RBD bind to a Rnd-family Rho-GTPases along with plexin dimerization and semaphoring binding, the intracellular segment undergoes conformational changes which allow the separate GAP domains to interact and become active in turning Rap family Rho-GTPases.{{cite journal | vauthors = Zhang L, Polyansky A, Buck M | title = Modeling transmembrane domain dimers/trimers of plexin receptors: implications for mechanisms of signal transmission across the membrane | journal = PLOS ONE | volume = 10 | issue = 4 | pages = e0121513 | date = 2015-04-02 | pmid = 25837709 | pmc = 4383379 | doi = 10.1371/journal.pone.0121513 | bibcode = 2015PLoSO..1021513Z | doi-access = free }} These GTPases can have a number of downstream effects, but in particular to Plexin expressed on axonal growth cones, the concentration the secondary messenger cyclic guanosine monophosphate (cGMP) increases within the cell.

Nine genes have been identified which divide plexins into four subclasses based on structure and homology. These genes include:

• Class A: PLXNA1, PLXNA2, PLXNA3, PLXNA4A
• Class B: PLXNB1, PLXNB2, PLXNB3
• Class C: {{Gene|PLXNC1}}
• Class D: PLXND1

Class A plexins interact with neuropilin co-receptor proteins to strengthen semaphorin binding interactions without altering the mode of binding.{{cite journal | vauthors = Gu C, Giraudo E | title = The role of semaphorins and their receptors in vascular development and cancer | journal = Experimental Cell Research | volume = 319 | issue = 9 | pages = 1306–16 | date = May 2013 | pmid = 23422037 | pmc = 3648602 | doi = 10.1016/j.yexcr.2013.02.003 }} The structure of the Class B plexins has an additional extracellular site for cleavage by convertases, enzymes which modify plexin precursor polypeptides into their final peptide sequence, as well as a structural PDZ interaction motif on its C-terminus.{{Citation needed|date=February 2024}} C-class plexins have fewer structural Methionine-Related Sequences (MRS) and IPT domains. D-class plexins have an additional modification in one of the MRS domains{{cite journal | vauthors = Perälä N, Sariola H, Immonen T | title = More than nervous: the emerging roles of plexins | journal = Differentiation; Research in Biological Diversity | volume = 83 | issue = 1 | pages = 77–91 | date = January 2012 | pmid = 22099179 | doi = 10.1016/j.diff.2011.08.001 }}

Plexin receptors largely act to signal the binding of semaphorin signaling proteins in a short-distance inhibitory manner. Each class of plexin has a range of specificity, meaning they could bind specifically to one or more semaphorin isomers. Plexins also have varying effects on development depending on their expression in different tissue types. Plexin receptors have implications in neural development and axon growth guidance, angiogenesis and heart development, skeletal and kidney morphogenesis, and in the immune system.{{cite journal | vauthors = Fujisawa H, Ohta K, Kameyama T, Murakami Y | title = Function of a cell adhesion molecule, plexin, in neuron network formation | journal = Developmental Neuroscience | volume = 19 | issue = 1 | pages = 101–5 | date = 1997 | pmid = 9078440 | doi = 10.1159/000111192 }} Genetic knockout of plexins have shown to be lethal at embryonic stages due to severe developmental defects in body systems regulated by semaphorin-plexin signaling. Malfunction of the plexin signaling pathway has been implicated in human diseases including neurological disorders and cancers.{{cite journal | vauthors = Sakurai A, Doçi CL, Doci C, Gutkind JS | title = Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer | journal = Cell Research | volume = 22 | issue = 1 | pages = 23–32 | date = January 2012 | pmid = 22157652 | pmc = 3351930 | doi = 10.1038/cr.2011.198 }}{{cite journal | vauthors = Tamagnone L | title = Emerging role of semaphorins as major regulatory signals and potential therapeutic targets in cancer | journal = Cancer Cell | volume = 22 | issue = 2 | pages = 145–52 | date = August 2012 | pmid = 22897846 | doi = 10.1016/j.ccr.2012.06.031 | doi-access = free }}{{cite journal | vauthors = Neufeld G, Mumblat Y, Smolkin T, Toledano S, Nir-Zvi I, Ziv K, Kessler O | title = The semaphorins and their receptors as modulators of tumor progression | journal = Drug Resistance Updates | volume = 29 | pages = 1–12 | date = November 2016 | pmid = 27912840 | doi = 10.1016/j.drup.2016.08.001 }}

{{Further|Axon guidance}}

• Plexin receptors on axon growth cones receive local semaphorin signaling and impede growth in that direction.
• Plexin activation on growth cones results in actin and microtubule polymer destabilization as well as clathrin-mediated endocytosis, resulting in retraction of growth cone projections.{{cite journal | vauthors = Akiyama H, Fukuda T, Tojima T, Nikolaev VO, Kamiguchi H | title = Cyclic Nucleotide Control of Microtubule Dynamics for Axon Guidance | journal = The Journal of Neuroscience | volume = 36 | issue = 20 | pages = 5636–49 | date = May 2016 | pmid = 27194341 | doi = 10.1523/JNEUROSCI.3596-15.2016 | pmc = 6601770 | doi-access = free }}

• PLXND1 is involved in guiding the growth of new blood vessels. Cells expressing Sema3E do not need additional vascularization. Developing vessels will have their growth towards these cells inhibited upon PLXND1 binding to Sema3E independent of Neuropilin.
• PLXNA2 and PLXND1 modulate proper development of cardiac structures.

• During development, PLXNA1 and PLXNA2 are expressed in chondrocytes and osteoblasts, implementing them in regulating bone homeostasis.
• PLXND1 has a role in the formation of vertebral bodies of the spinal column by signaling for proper fusing and splitting of the axial elements.
• PLXNB1 and PLXNB2 control branching of the ureter in the kidney by inhibiting and promoting it, respectively.

• PLXNA1 promotes dendritic and T cell proliferation.
• PLXNA4 inhibits T cell response, but promotes inflammatory cytokine production by macrophages.
• PLXNB1 promotes B cell survival, as well as macrophage recruitment.

In a genome-wide association study, plexins, which are mutated in several monogenic neurodevelopmental disorders, were significantly enriched for associations with high IQ.{{Cite journal|last1=Zabaneh|first1=D.|last2=Krapohl|first2=E.|last3=Gaspar|first3=H. A.|last4=Curtis|first4=C.|last5=Lee|first5=S. H.|last6=Patel|first6=H.|last7=Newhouse|first7=S.|last8=Wu|first8=H. M.|last9=Simpson|first9=M. A.|last10=Putallaz|first10=M.|last11=Lubinski|first11=D.|date=May 2018|title=A genome-wide association study for extremely high intelligence|url= |journal=Molecular Psychiatry|language=en|volume=23|issue=5|pages=1226–1232|doi=10.1038/mp.2017.121|issn=1476-5578|pmc=5987166|pmid=29731509}}

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Category:Single-pass transmembrane proteins