Plexin

Last updated
Plexin
Plxn.png
Plexin extracellular domain
Identifiers
SymbolPLXN
Pfam PF08337
InterPro IPR031148
Membranome 17
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

A plexin is a protein which acts as a receptor for semaphorin family signaling proteins. [1] [2] [3] It is classically known for its expression on the surface of axon growth cones and involvement in signal transduction to steer axon growth away from the source of semaphorin. [1] [4] Plexin also has implications in development of other body systems by activating GTPase enzymes to induce a number of intracellular biochemical changes leading to a variety of downstream effects. [5] [6]

Contents

Structure

Extracellular

All plexins have an extracellular SEMA domain at their N-terminus. [3] 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. [3] [7] This is followed by alternating plexin, semaphorin, and integrin (PSI) domains and immunoglobulin-like, plexin, and transcription factors (IPT) domains. [3] [8] Each of these is named for the proteins in which their structure is conserved. [9] [10] Collectively, the extracellular region resembles a curved stalk projecting in a clockwise direction. [8]

Before bindings its semaphorin dimer ligand, associations between the extracellular domains of pre-formed plexin dimers keeps their intracellular domains segregated and inactive. [11] [12] This allows for co-localization of plexin dimers to be primed for binding of semaphorin dimers and activation of intracellular machinery. [3]

Intracellular

Highly conserved intracellular domains consisting of a bipartite segment which functions as a GTPase-Activating Protein (GAP). [3] Plexin is the only known receptor molecule to have a GAP domain. [7] In the inactive state, these two sections are separated by a Rho-GTPase binding domain (RBD). [7] 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. [7] [13] 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. [5] [6]

Classes

Nine genes have been identified which divide plexins into four subclasses based on structure and homology. [3] These genes include:

Class A plexins interact with neuropilin co-receptor proteins to strengthen semaphorin binding interactions without altering the mode of binding. [4] [7] [14] 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 ] 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 [8] [15]

Function

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. [15] [16] 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. [7] Malfunction of the plexin signaling pathway has been implicated in human diseases including neurological disorders and cancers. [14] [17] [18] [19]

Axon guidance

Angiogenesis and heart development

Skeletal and kidney development

Immune system

Role in intelligence

In a genome-wide association study, plexins, which are mutated in several monogenic neurodevelopmental disorders, were significantly enriched for associations with high IQ. [21]

Related Research Articles

Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they manage to find their way so accurately is an area of ongoing research.

A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before differentiation is complete.

<span class="mw-page-title-main">Low-affinity nerve growth factor receptor</span> Human protein-coding gene

The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic factor receptor. Neurotrophic factor receptors bind Neurotrophins including Nerve growth factor, Neurotrophin-3, Brain-derived neurotrophic factor, and Neurotrophin-4. All neurotrophins bind to p75NTR. This also includes the immature pro-neurotrophin forms. Neurotrophic factor receptors, including p75NTR, are responsible for ensuring a proper density to target ratio of developing neurons, refining broader maps in development into precise connections. p75NTR is involved in pathways that promote neuronal survival and neuronal death.

Semaphorins are a class of secreted and membrane proteins that were originally identified as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. Semaphorins are usually cues to deflect axons from inappropriate regions, especially important in the neural system development. The major class of proteins that act as their receptors are called plexins, with neuropilins as their co-receptors in many cases. The main receptors for semaphorins are plexins, which have established roles in regulating Rho-family GTPases. Recent work shows that plexins can also influence R-Ras, which, in turn, can regulate integrins. Such regulation is probably a common feature of semaphorin signalling and contributes substantially to our understanding of semaphorin biology.

<span class="mw-page-title-main">Neuropilin</span> Protein receptor active in neurons

Neuropilin is a protein receptor active in neurons.

<span class="mw-page-title-main">VEGF receptor</span> Protein family

VEGF receptors (VEGFRs) are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Depending on alternative splicing, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR).

<span class="mw-page-title-main">Neuropilin 2</span> Protein-coding gene in the species Homo sapiens

Neuropilin 2 (NRP2) is a protein that in humans is encoded by the NRP2 gene.

<span class="mw-page-title-main">Sema domain</span>

The Sema domain is a structural domain of semaphorins, which are a large family of secreted and transmembrane proteins, some of which function as repellent signals during axon guidance. Sema domains also occur in the hepatocyte growth factor receptor, Plexin-A3 and in viral proteins.

<span class="mw-page-title-main">Neuropilin 1</span> Protein-coding gene in the species Homo sapiens

Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene. In humans, the neuropilin 1 gene is located at 10p11.22. This is one of two human neuropilins.

<span class="mw-page-title-main">Semaphorin-3A</span> Protein-coding gene in the species Homo sapiens

Semaphorin-3A is a protein that in humans is encoded by the SEMA3A gene.

<span class="mw-page-title-main">SEMA4D</span>

Semaphorin-4D (SEMA4D) also known as Cluster of Differentiation 100 (CD100), is a protein of the semaphorin family that in humans is encoded by the SEMA4D gene.

<span class="mw-page-title-main">PLXNB1</span> Protein-coding gene in the species Homo sapiens

Plexin B1 is a protein of the plexin family that in humans is encoded by the PLXNB1 gene.

<span class="mw-page-title-main">PTPRM</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the PTPRM gene.

<span class="mw-page-title-main">SEMA3F</span> Protein-coding gene in the species Homo sapiens

Semaphorin-3F is a protein that in humans is encoded by the SEMA3F gene.

<span class="mw-page-title-main">Rnd1</span> Protein-coding gene in the species Homo sapiens

Rnd1 is a small signaling G protein, and is a member of the Rnd subgroup of the Rho family of GTPases. It is encoded by the gene RND1.

<span class="mw-page-title-main">Plexin A1</span> Protein-coding gene in the species Homo sapiens

Plexin-A1 is a protein that in humans is encoded by the PLXNA1 gene.

<span class="mw-page-title-main">PLXNA2</span> Protein-coding gene in the species Homo sapiens

Plexin-A2 is a protein that in humans is coded by the PLXNA2 gene.

<span class="mw-page-title-main">PLXNA4A</span> Protein-coding gene in the species Homo sapiens

Plexin-A4 is a protein that in humans is encoded by the PLXNA4 gene.

Collapsin response mediator protein family or CRMP family consists of five intracellular phosphoproteins of similar molecular size and high (50–70%) amino acid sequence identity. CRMPs are predominantly expressed in the nervous system during development and play important roles in axon formation from neurites and in growth cone guidance and collapse through their interactions with microtubules. Cleaved forms of CRMPs have also been linked to neuron degeneration after trauma induced injury.

<span class="mw-page-title-main">Tropic cues involved in growth cone guidance</span>

The growth cone is a highly dynamic structure of the developing neuron, changing directionality in response to different secreted and contact-dependent guidance cues; it navigates through the developing nervous system in search of its target. The migration of the growth cone is mediated through the interaction of numerous trophic and tropic factors; netrins, slits, ephrins and semaphorins are four well-studied tropic cues (Fig.1). The growth cone is capable of modifying its sensitivity to these guidance molecules as it migrates to its target; this sensitivity regulation is an important theme seen throughout development.

References

  1. 1 2 Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia AS, White LE (2012). Neuroscience (5th ed.). Sunderland, Mass.: Sinauer Associates. pp. 517–518. ISBN   978-0-87893-646-5. OCLC   754389847.
  2. ↑ Winberg ML, Noordermeer JN, Tamagnone L, Comoglio PM, Spriggs MK, Tessier-Lavigne M, Goodman CS (December 1998). "Plexin A is a neuronal semaphorin receptor that controls axon guidance". Cell. 95 (7): 903–16. doi: 10.1016/S0092-8674(00)81715-8 . PMID   9875845.
  3. 1 2 3 4 5 6 7 Kong Y, Janssen BJ, Malinauskas T, Vangoor VR, Coles CH, Kaufmann R, Ni T, Gilbert RJ, Padilla-Parra S, Pasterkamp RJ, Jones EY (August 2016). "Structural Basis for Plexin Activation and Regulation". Neuron. 91 (3): 548–60. doi:10.1016/j.neuron.2016.06.018. PMC   4980550 . PMID   27397516.
  4. 1 2 Janssen BJ, Malinauskas T, Weir GA, Cader MZ, Siebold C, Jones EY (December 2012). "Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex". Nature Structural & Molecular Biology. 19 (12): 1293–9. doi:10.1038/nsmb.2416. PMC   3590443 . PMID   23104057.
  5. 1 2 Ellenbroek SI, Collard JG (November 2007). "Rho GTPases: functions and association with cancer". Clinical & Experimental Metastasis. 24 (8): 657–72. doi:10.1007/s10585-007-9119-1. PMID   18000759. S2CID   680659.
  6. 1 2 Ayoob JC, Yu HH, Terman JR, Kolodkin AL (July 2004). "The Drosophila receptor guanylyl cyclase Gyc76C is required for semaphorin-1a-plexin A-mediated axonal repulsion". The Journal of Neuroscience. 24 (30): 6639–49. doi: 10.1523/JNEUROSCI.1104-04.2004 . PMC   6729715 . PMID   15282266.
  7. 1 2 3 4 5 6 Pascoe HG, Wang Y, Zhang X (September 2015). "Structural mechanisms of plexin signaling". Progress in Biophysics and Molecular Biology. 118 (3): 161–8. doi:10.1016/j.pbiomolbio.2015.03.006. PMC   4537802 . PMID   25824683.
  8. 1 2 3 Suzuki K, Tsunoda H, Omiya R, Matoba K, Baba T, Suzuki S, Segawa H, Kumanogoh A, Iwasaki K, Hattori K, Takagi J (June 2016). "Structure of the Plexin Ectodomain Bound by Semaphorin-Mimicking Antibodies". PLOS ONE. 11 (6): e0156719. Bibcode:2016PLoSO..1156719S. doi: 10.1371/journal.pone.0156719 . PMC   4892512 . PMID   27258772.
  9. ↑ Messina A, Giacobini P (September 2013). "Semaphorin signaling in the development and function of the gonadotropin hormone-releasing hormone system". Frontiers in Endocrinology. 4: 133. doi: 10.3389/fendo.2013.00133 . PMC   3779810 . PMID   24065959.
  10. ↑ Kozlov G, Perreault A, Schrag JD, Park M, Cygler M, Gehring K, Ekiel I (August 2004). "Insights into function of PSI domains from structure of the Met receptor PSI domain". Biochemical and Biophysical Research Communications. 321 (1): 234–40. doi:10.1016/j.bbrc.2004.06.132. PMID   15358240.
  11. ↑ Takahashi T, Strittmatter SM (February 2001). "Plexina1 autoinhibition by the plexin sema domain". Neuron. 29 (2): 429–39. doi: 10.1016/S0896-6273(01)00216-1 . PMID   11239433.
  12. ↑ Marita M, Wang Y, Kaliszewski MJ, Skinner KC, Comar WD, Shi X, Dasari P, Zhang X, Smith AW (November 2015). "Class A Plexins Are Organized as Preformed Inactive Dimers on the Cell Surface". Biophysical Journal. 109 (9): 1937–45. Bibcode:2015BpJ...109.1937M. doi:10.1016/j.bpj.2015.04.043. PMC   4643210 . PMID   26536270.
  13. ↑ Zhang L, Polyansky A, Buck M (2015-04-02). "Modeling transmembrane domain dimers/trimers of plexin receptors: implications for mechanisms of signal transmission across the membrane". PLOS ONE. 10 (4): e0121513. Bibcode:2015PLoSO..1021513Z. doi: 10.1371/journal.pone.0121513 . PMC   4383379 . PMID   25837709.
  14. 1 2 Gu C, Giraudo E (May 2013). "The role of semaphorins and their receptors in vascular development and cancer". Experimental Cell Research. 319 (9): 1306–16. doi:10.1016/j.yexcr.2013.02.003. PMC   3648602 . PMID   23422037.
  15. 1 2 3 4 5 Perälä N, Sariola H, Immonen T (January 2012). "More than nervous: the emerging roles of plexins". Differentiation; Research in Biological Diversity. 83 (1): 77–91. doi:10.1016/j.diff.2011.08.001. PMID   22099179.
  16. 1 2 Fujisawa H, Ohta K, Kameyama T, Murakami Y (1997). "Function of a cell adhesion molecule, plexin, in neuron network formation". Developmental Neuroscience. 19 (1): 101–5. doi:10.1159/000111192. PMID   9078440.
  17. ↑ Sakurai A, Doçi CL, Doci C, Gutkind JS (January 2012). "Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer". Cell Research. 22 (1): 23–32. doi:10.1038/cr.2011.198. PMC   3351930 . PMID   22157652.
  18. ↑ Tamagnone L (August 2012). "Emerging role of semaphorins as major regulatory signals and potential therapeutic targets in cancer". Cancer Cell. 22 (2): 145–52. doi: 10.1016/j.ccr.2012.06.031 . PMID   22897846.
  19. ↑ Neufeld G, Mumblat Y, Smolkin T, Toledano S, Nir-Zvi I, Ziv K, Kessler O (November 2016). "The semaphorins and their receptors as modulators of tumor progression". Drug Resistance Updates. 29: 1–12. doi:10.1016/j.drup.2016.08.001. PMID   27912840.
  20. ↑ Akiyama H, Fukuda T, Tojima T, Nikolaev VO, Kamiguchi H (May 2016). "Cyclic Nucleotide Control of Microtubule Dynamics for Axon Guidance". The Journal of Neuroscience. 36 (20): 5636–49. doi: 10.1523/JNEUROSCI.3596-15.2016 . PMC   6601770 . PMID   27194341.
  21. ↑ Zabaneh, D.; Krapohl, E.; Gaspar, H. A.; Curtis, C.; Lee, S. H.; Patel, H.; Newhouse, S.; Wu, H. M.; Simpson, M. A.; Putallaz, M.; Lubinski, D. (May 2018). "A genome-wide association study for extremely high intelligence". Molecular Psychiatry. 23 (5): 1226–1232. doi:10.1038/mp.2017.121. ISSN   1476-5578. PMC   5987166 . PMID   29731509.
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