Abstract
The biological activities of the semaphorins and their receptors depend on their structural properties and atomic-level interactions. This chapter reviews our current knowledge of molecular architecture and interactions with the aim of identifying features and properties that fit the semaphorins and their receptors for biological function. Structural analyses of the hallmark sema domain in semaphorins have revealed a seven-bladed β-propeller with distinctive elaborations that mediate dimerization as well as receptor binding. The plexins, the major family of semaphorin receptors, are also distinguished by the presence of an N-terminal sema domain in their ectodomain. In plexins the sema domain fold is modified to serve as a monomeric platform for interactions with semaphorin ligands and co-receptors. In the recognition complex between semaphorin and plexin, the dimeric semaphorin acts as a crosslink to juxtapose two plexin receptors. The role of extracellular dimerization in triggering signaling appears to be mirrored inside the cell by dimerization-driven activation of the plexin cytoplasmic segment. The architecture of the cytoplasmic segment is novel in comprising a small RhoGTPase-binding domain inserted into a GTPase-activating protein (GAP)-type topology. The functional properties of this unique signal transducer are beginning to emerge, but the mode of signaling is one of many aspects of the semaphorin–plexin system that still pose fascinating questions. In addition to surveying our current state of knowledge, this chapter delineates the limits of our understanding of molecular mechanism in semaphorin biology.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Adams RH, Lohrum M, Klostermann A, Betz H, Püschel AW (1997) The chemorepulsive activity of secreted semaphorins is regulated by furin-dependent proteolytic processing. EMBO J 16:6077–6086
Antipenko A, Himanen JP, van Leyen K, Nardi-Dei V, Lesniak J, Barton WA et al (2003) Structure of the semaphorin-3A receptor binding module. Neuron 39:589–598
Appleton BA, Wu P, Maloney J, Yin J, Liang WC, Stawicki S et al (2007) Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding. EMBO J 26:4902–4912
Aricescu AR, Hon WC, Siebold C, Lu W, van der Merwe PA, Jones EY (2006) Molecular analysis of receptor protein tyrosine phosphatase mu-mediated cell adhesion. EMBO J 25:701–712
Aricescu AR, Siebold C, Choudhuri K, Chang VT, Lu W, Davis SJ, van der Merwe PA, Jones EY (2007) Structure of a tyrosine phosphatase adhesive interaction reveals a spacer-clamp mechanism. Science 317:1217–1220
Arneja A, Johnson H, Gabrovsek L, Lauffenburger DA, White FM (2014) Qualitatively different T cell phenotypic responses to IL-2 versus IL-15 are unified by identical dependences on receptor signal strength and duration. J Immunol 192:123–135
Atanasova M, Whitty A (2012) Understanding cytokine and growth factor receptor activation mechanisms. Crit Rev Biochem Mol Biol 47:502–530
Bell CH, Aricescu AR, Jones EY, Siebold C (2011) A dual binding mode for RhoGTPases in plexin signalling. PLoS Biol 9:e1001134
Bernards A, Settleman J (2004) GAP control: regulating the regulators of small GTPases. Trends Cell Biol 14:377–385
Bork P, Doerks T, Springer TA, Snel B (1999) Domains in plexins: links to integrins and transcription factors. Trends Biochem Sci 24:261–263
Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, Mazzone M (2013) Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24:695–709
Chao KL, Tsai IW, Chen C, Herzberg O (2012) Crystal structure of the Sema-PSI extracellular domain of human RON receptor tyrosine kinase. PLoS One 7:e41912
Chauvet S, Cohen S, Yoshida Y, Fekrane L, Livet J, Gayet O, Segu L, Buhot MC, Jessell TM, Henderson CE, Mann F (2007) Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development. Neuron 56:807–822
Chen H, He Z, Bagri A, Tessier-Lavigne M (1998) Semaphorin-neuropilin interactions underlying sympathetic axon responses to class III semaphorins. Neuron 21:1283–1290
Chen CK, Chan NL, Wang AH (2011) The many blades of the β-propeller proteins: conserved but versatile. Trends Biochem Sci 36:553–561
Coles CH, Shen Y, Tenney AP, Siebold C, Sutton GC, Lu W, Gallagher JT, Jones EY, Flanagan JG, Aricescu AR (2011) Proteoglycan-specific molecular switch for RPTPσ clustering and neuronal extension. Science 332:484–488
Fülöp V, Jones DT (1999) Beta propellers: structural rigidity and functional diversity. Curr Opin Struct Biol 9:715–721
Gherardi E, Youles ME, Miguel RN, Blundell TL, Iamele L, Gough J et al (2003) Functional map and domain structure of MET, the product of the c-met protooncogene and receptor for hepatocyte growth factor/scatter factor. Proc Natl Acad Sci USA 100:12039–12044
Gherardi E, Love CA, Esnouf RM, Jones EY (2004) The sema domain. Curr Opin Struct Biol 14:669–678
Giger RJ, Urquhart ER, Gillespie SK, Levengood DV, Ginty DD, Kolodkin AL (1998) Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity. Neuron 21:1079–1092
Gu C, Rodriguez ER, Reimert DV, Shu T, Fritzsch B, Richards LJ, Kolodkin AL, Ginty DD (2003) Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev Cell 5:45–57
Guo HF, Li X, Parker MW, Waltenberger J, Becker PM, Vander Kooi CW (2013) Mechanistic basis for the potent anti-angiogenic activity of semaphorin 3F. Biochemistry 52:7551–7558
He Z, Tessier-Lavigne M (1997) Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell 90:739–751
He H, Yang T, Terman JR, Zhang X (2009) Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration. Proc Natl Acad Sci USA 106:15610–15615
Hota PK, Buck M (2009) Thermodynamic characterization of two homologous protein complexes: associations of the semaphorin receptor plexin-B1 RhoGTPase binding domain with Rnd1 and active Rac1. Protein Sci 18:1060–1071
Hota PK, Buck M (2012) Plexin structures are coming: opportunities for multilevel investigations of semaphorin guidance receptors, their cell signaling mechanisms, and functions. Cell Mol Life Sci 69:3765–3805
Hung RJ, Pak CW, Terman JR (2011) Direct redox regulation of F-actin assembly and disassembly by Mical. Science 334:1710–1713
Janes PW, Nievergall E, Lackmann M (2012) Concepts and consequences of Eph receptor clustering. Semin Cell Dev Biol 23:43–50
Janssen BJ, Robinson RA, Pérez-Brangulí F, Bell CH, Mitchell KJ, Siebold C et al (2010) Structural basis of semaphorin-plexin signalling. Nature 467:1118–1122
Janssen BJC, Malinauskas T, Weir GA, Cader MZ, Siebold C, Jones EY (2012) Neuropilins lock secreted semaphorins onto plexins in a ternary signalling complex. Nat Struct Mol Biol 19:1293–1299
Kalie E, Jaitin DA, Podoplelova Y, Piehler J, Schreiber G (2008) The stability of the ternary interferon-receptor complex rather than the affinity to the individual subunits dictates differential biological activities. J Biol Chem 283:32925–32936
Kantor DB, Chivatakarn O, Peer KL, Oster SF, Inatani M, Hansen MJ, Flanagan JG, Yamaguchi Y, Sretavan DW, Giger RJ, Kolodkin AL (2004) Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 44:961–975
Kigel B, Rabinowicz N, Varshavsky A, Kessler O, Neufeld G (2011) Plexin-A4 promotes tumor progression and tumor angiogenesis by enhancement of VEGF and bFGF signaling. Blood 118:4285–4296
Klostermann A, Lohrum M, Adams RH, Püschel AW (1998) The chemorepulsive activity of the axonal guidance signal semaphorin D requires dimerization. J Biol Chem 273:7326–7331
Kolodkin AL, Matthes DJ, Goodman CS (1993) The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75:1389–1399
Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD (1997) Neuropilin is a semaphorin III receptor. Cell 90:753–762
Koppel AM, Raper JA (1998) Collapsin-1 covalently dimerizes, and dimerization is necessary for collapsing activity. J Biol Chem 273:15708–15713
Kozlov G, Perreault A, Schrag JD, Park M, Cygler M, Gehring K et al (2004) Insights into function of PSI domains from structure of the Met receptor PSI domain. Biochem Biophys Res Commun 321:234–240
Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141:1117–1134
Liu H, Juo ZS, Shim AH, Focia PJ, Chen X, Garcia KC et al (2010) Structural basis of semaphorin-plexin recognition and viral mimicry from Sema7A and A39R complexes with PlexinC1. Cell 142:749–761
Love CA, Harlos K, Mavaddat N, Davis SJ, Stuart DI, Jones EY et al (2003) The ligand-binding face of the semaphorins revealed by the high resolution crystal structure of SEMA4D. Nat Struct Biol 10:843–848
Luo BH, Carman CV, Springer TA (2007) Structural basis of integrin regulation and signaling. Annu Rev Immunol 25:619–647
Moraga I, Spangler J, Mendoza JL, Garcia KC (2014) Multifarious determinants of cytokine receptor signaling specificity. Adv Immunol 121:1–39
Nadella M, Bianchet MA, Gabelli SB, Barrila J, Amzel LM (2005) Structure and activity of the axon guidance protein MICAL. Proc Natl Acad Sci USA 102:16830–16835
Nakamura F, Tanaka M, Takahashi T, Kalb RG, Strittmatter SM (1998) Neuropilin-1 extracellular domains mediate semaphorin D/III-induced growth cone collapse. Neuron 21:1093–1100
Niemann HH, Jäger V, Butler PJ, van den Heuvel J, Schmidt S, Ferraris D et al (2007) Structure of the human receptor tyrosine kinase met in complex with the Listeria invasion protein InlB. Cell 130:235–246
Nogi T, Yasui N, Mihara E, Matsunaga Y, Noda M, Yamashita N et al (2010) Structural basis for semaphorin signalling through the plexin receptor. Nature 467:1123–1127
Oinuma I, Ishikawa Y, Katoh H, Negishi M (2004a) The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science 305:862–865
Oinuma I, Katoh H, Negishi M (2004b) Molecular dissection of the semaphorin 4D receptor plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons. J Neurosci 24:11473–11480
Raimondi C, Ruhrberg C (2013) Neuropilin signalling in vessels, neurons and tumours. Semin Cell Dev Biol 24:172–178
Renaud J, Kerjan G, Sumita I, Zagar Y, Georget V, Kim D et al (2008) Plexin-A2 and its ligand, Sema6A, control nucleus-centrosome coupling in migrating granule cells. Nat Neurosci 11:440–449
Scheffzek K, Ahmadian MR (2005) GTPase activating proteins: structural and functional insights 18 years after discovery. Cell Mol Life Sci 62:3014–3038
Seiradake E, Harlos K, Sutton G, Aricescu AR, Jones EY (2010) An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly. Nat Struct Mol Biol 17:398–402
Seiradake E, Schaupp A, del Toro Ruiz D, Kaufmann R, Mitakidis N, Harlos K, Aricescu AR, Klein R, Jones EY (2013) Structurally encoded intraclass differences in EphA clusters drive distinct cell responses. Nat Struct Mol Biol 20:958–964
Sharma A, Verhaagen J, Harvey AR (2012) Receptor complexes for each of the Class 3 Semaphorins. Front Cell Neurosci 6:28
Siebold C, Jones EY (2013) Structural insights into semaphorins and their receptors. Semin Cell Dev Biol 24:139–145
Siebold C, Berrow N, Walter TS, Harlos K, Owens RJ, Stuart DI et al (2005) High-resolution structure of the catalytic region of MICAL, a multi-domain flavoenzyme-signaling molecule. Proc Natl Acad Sci USA 102:16836–16841
Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735–745
Sot B, Kötting C, Deaconescu D, Suveyzdis Y, Gerwert K, Wittinghofer A (2010) Unravelling the mechanism of dual-specificity GAPs. EMBO J 29:1205–1214
Stamos J, Lazarus RA, Yao X, Kirchhofer D, Wiesmann C (2004) Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor. EMBO J 23:2325–2335
Takahashi T, Strittmatter SM (2001) Plexina1 autoinhibition by the plexin sema domain. Neuron 29:429–439
Takahashi T, Fournier A, Nakamura F, Wang LH, Murakami Y, Kalb RG et al (1999) Plexin–neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 99:59–69
Tamagnone L, Artigiani S, Chen H, He Z, Ming GI, Song H et al (1999) Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99:71–80
Terman JR, Mao T, Pasterkamp RJ, Yu HH, Kolodkin AL (2002) MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion. Cell 109:887–900
Thomas C, Moraga I, Levin D, Krutzik PO, Podoplelova Y, Trejo A, Lee C, Yarden G, Vleck SE, Glenn JS, Nolan GP, Piehler J, Schreiber G, Garcia KC (2011) Structural linkage between ligand discrimination and receptor activation by type I interferons. Cell 146:621–632
Tong Y, Buck M (2005) 1H, 15N and 13C Resonance assignments and secondary structure determination reveal that the minimal Rac1 GTPase binding domain of plexin-B1 has a ubiquitin fold. J Biomol NMR 31:369–370
Tong Y, Chugha P, Hota PK, Alviani RS, Li M, Tempel W et al (2007) Binding of Rac1, Rnd1, and RhoD to a novel Rho GTPase interaction motif destabilizes dimerization of the plexin-B1 effector domain. J Biol Chem 282:37215–37224
Tong Y, Hota PK, Penachioni JY, Hamaneh MB, Kim S, Alviani RS et al (2009) Structure and function of the intracellular region of the plexin-b1 transmembrane receptor. J Biol Chem 284:35962–35972
Turner LJ, Nicholls S, Hall A (2004) The activity of the plexin-A1 receptor is regulated by Rac. J Biol Chem 279:33199–33205
Vander Kooi CW, Jusino MA, Perman B, Neau DB, Bellamy HD, Leahy DJ (2007) Structural basis for ligand and heparin binding to neuropilin B domains. Proc Natl Acad Sci USA 104:6152–6157
Wang H, Hota PK, Tong Y, Li B, Shen L, Nedyalkova L et al (2011) Structural basis of Rnd1 binding to plexin Rho GTPase binding domains (RBDs). J Biol Chem 286:26093–26106
Wang Y, He H, Srivastava N, Vikarunnessa S, Chen YB, Jiang J et al (2012) Plexins are GTPase-activating proteins for Rap and are activated by induced dimerization. Sci Signal 5:ra6
Wang Y, Pascoe HG, Brautigam CA, He H, Zhang X (2013) Structural basis for activation and non-canonical catalysis of the Rap GTPase activating protein domain of plexin. Elife 2:e01279
Winberg ML, Noordermeer JN, Tamagnone L, Comoglio PM, Spriggs MK, Tessier-Lavigne M et al (1998) Plexin A is a neuronal semaphorin receptor that controls axon guidance. Cell 95:903–916
Worzfeld T, Swiercz JM, Sentürk A, Genz B, Korostylev A, Deng S, Xia J, Hoshino M, Epstein JA, Chan AM, Vollmar B, Acker-Palmer A, Kuner R, Offermanns S (2014) Genetic dissection of plexin signaling in vivo. Proc Natl Acad Sci USA 111:2194–2199
Xiao T, Takagi J, Coller BS, Wang JH, Springer TA (2004) Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 432:59–67
Zhou Y, Gunput RA, Pasterkamp RJ (2008) Semaphorin signaling: progress made and promises ahead. Trends Biochem Sci 33:161–170
Acknowledgments
E.Y.J. is funded by Cancer Research UK and the UK Medical Research Council.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Japan
About this chapter
Cite this chapter
Jones, E.Y. (2015). Structure of Semaphorins and Their Receptors. In: Kumanogoh, A. (eds) Semaphorins. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54385-5_5
Download citation
DOI: https://doi.org/10.1007/978-4-431-54385-5_5
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-54384-8
Online ISBN: 978-4-431-54385-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)