BioPAX pathway converted from "Tropoelastin associates with microfibrils" in the Reactome database.LEFT-TO-RIGHTTropoelastin associates with microfibrilsElastin, the highly insoluble core protein of elastic fibers, is secreted as a soluble protein monomer referred to as tropoelastin. Under physiological conditions the monomers phase separate and coalesce into spherical packages (Clarke et al. 2006), a process known as coacervation. Packages of accumulated elastin are delivered to fibrillin-based fibres in a mechanism that is correlated with cell migration during embryonic development (Czirok et al. 2006). A transglutaminase cross-link between domain 4 of tropoelastin and domain 16 of fibrillin-1 (FBN1) may stabilize initial deposition (Clarke et al. 2005). Elastin is subsequently cross linked by members of the lysyl oxidase family via lysine residues, resulting in mature, insoluble fibres (Sato et al. 2007, Wise & Weiss 2009).<br><br>Fibulin-5 (FBLN5) expressed by vascular smooth muscle cells plays an essential role in the formation of elastic fibres, mediating interactions between elastin and fibrillin (Yanigasawa et al. 2002, Freeman et al. 2005). FBLN5 binds tropoelastin but not mature elastin (Zheng et al. 2007), regulating coacervation (Yanigasawa et al. 2009). FBLN5 can bind FBN1 monomers and fibrils (Freeman et al. 2005), but it is not clear whether this is necessary for elastin polymerization. FBLN5 also binds elastin cross-linking enzymes lysyl oxidase like (LOXL)-1, -2, and -4 (Hirai et al. 2007). Overexpression of Fbln5 increases elastin deposition and formation of desmosine cross-links (Nonaka et al. 2009). EMILIN can affect the process of elastic fibre formation (Bressan et al. 1993). It binds elastin and fibulin-5 and appears to coordinate their common interaction (Zanetti et al. 2004).Authored: Jupe, S, 2012-04-30Reviewed: Muiznieks, Lisa, 2012-11-02Edited: Jupe, S, 2012-11-12FBLN5Fibulin-5FBLN5_HUMANReactome DB_ID: 2161278extracellular regionGENE ONTOLOGYGO:0005576UniProt:Q9UBX5 FBLN5FBLN5DANCEUNQ184/PRO210FUNCTION Essential for elastic fiber formation, is involved in the assembly of continuous elastin (ELN) polymer and promotes the interaction of microfibrils and ELN (PubMed:18185537). Stabilizes and organizes elastic fibers in the skin, lung and vasculature (By similarity). Promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. Vascular ligand for integrin receptors which may play a role in vascular development and remodeling (PubMed:10428823). May act as an adapter that mediates the interaction between FBN1 and ELN (PubMed:17255108).SUBUNIT Homodimer (PubMed:20007835). Monomer (PubMed:15790312, PubMed:19617354), homodimerizes in presence of Ca(2+) (PubMed:19617354). Interacts with ELN (PubMed:17035250, PubMed:15790312). Interacts (via N-terminus) with the integrins ITGAV/ITGB3, ITGAV/ITGB5 and ITGA9/ITGB1 (By similarity). Interacts with FBN1 (via N-terminal domain). Forms a ternary complex with ELN and FBN1 (PubMed:17255108). Interacts with EFEMP2 with moderate affinity (PubMed:19570982).TISSUE SPECIFICITY Expressed in skin fibroblasts (at protein level)(PubMed:17035250). Expressed predominantly in heart, ovary, and colon but also in kidney, pancreas, testis, lung and placenta. Not detectable in brain, liver, thymus, prostate, or peripheral blood leukocytes (PubMed:10428823).PTM N-glycosylated.SIMILARITY Belongs to the fibulin family.Homo sapiensNCBI Taxonomy9606UniProtQ9UBX524EQUAL448EQUALReactome Database ID Release 762161278Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161278ReactomeR-HSA-21612781Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161278.1Reactomehttp://www.reactome.orgFibrilins:MFAP2,MFAP5Reactome DB_ID: 2396329Converted from EntitySet in ReactomeMFAP2, MFAP5Reactome DB_ID: 2396477MFAP2MAGP1Microfibrillar-associated protein 2MFAP2_HUMANReactome DB_ID: 2161346UniProt:P55001 MFAP2MFAP2MAGP1FUNCTION Component of the elastin-associated microfibrils.SUBUNIT Forms a ternary complex with BGN and ELN. Interacts with FBN1 (via N-terminal domain) and FBN2.PTM Forms intermolecular disulfide bonds either with other MAGP-1 molecules or with other components of the microfibrils. May form transglutaminase cross-links.PTM O-glycosylated.SIMILARITY Belongs to the MFAP family.UniProtP5500118EQUAL183EQUALReactome Database ID Release 762161346Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161346ReactomeR-HSA-21613461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161346.1MFAP5MAGP2Microfibrillar-associated protein 5MFAP5_HUMANReactome DB_ID: 2161230UniProt:Q13361 MFAP5MFAP5MAGP2FUNCTION May play a role in hematopoiesis. In the cardiovascular system, could regulate growth factors or participate in cell signaling in maintaining large vessel integrity (By similarity). Component of the elastin-associated microfibrils (PubMed:8557636).SUBUNIT Interacts with TGFB2. Interacts with BMP2. Interacts with FBN1 (via N-terminal domain) and FBN2.PTM Forms intermolecular disulfide bonds either with other MAGP-2 molecules or with other components of the microfibrils.PTM N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. O-glycan heterogeneity at Thr-54: HexHexNAc (major) and HexHexNAc + sulfate (minor).SIMILARITY Belongs to the MFAP family.UniProtQ1336122EQUAL173EQUALReactome Database ID Release 762161230Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161230ReactomeR-HSA-21612301Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161230.1Reactome Database ID Release 762396477Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2396477ReactomeR-HSA-23964771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2396477.11Converted from EntitySet in ReactomeFibrillin 1,2,(3)Reactome DB_ID: 2159839Fibrillin-1Reactome DB_ID: 2159874Reactome Database ID Release 762159874Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2159874ReactomeR-HSA-21598742Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2159874.2ChEBI36080additional informationMIMI:0361Fibrillin-2Reactome DB_ID: 2159861Reactome Database ID Release 762159861Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2159861ReactomeR-HSA-21598612Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2159861.2ChEBI36080Fibrillin-3Reactome DB_ID: 2159866Reactome Database ID Release 762159866Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2159866ReactomeR-HSA-21598662Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2159866.2ChEBI36080Reactome Database ID Release 762159839Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2159839ReactomeR-HSA-21598391Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2159839.11Reactome Database ID Release 762396329Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2396329ReactomeR-HSA-23963291Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2396329.1Tropoelastin aggregateReactome DB_ID: 2161342ELNTropoelastinELN_HUMANReactome DB_ID: 1454880UniProt:P15502 ELNELNFUNCTION Major structural protein of tissues such as aorta and nuchal ligament, which must expand rapidly and recover completely. Molecular determinant of the late arterial morphogenesis, stabilizing arterial structure by regulating proliferation and organization of vascular smooth muscle (By similarity).SUBUNIT The polymeric elastin chains are cross-linked together into an extensible 3D network. Forms a ternary complex with BGN and MFAP2. Interacts with MFAP2 via divalent cations (calcium &gt; magnesium &gt; manganese) in a dose-dependent and saturating manner. Interacts with FBLN5 (PubMed:15790312, PubMed:17035250). Interacts with FBN1 (PubMed:15790312). Forms a ternary complex with FBN1 and FBLN2 or FBLN5 (PubMed:17255108). Interacts with MFAP4 in a Ca (2+)-dependent manner; this interaction promotes ELN self-assembly (By similarity) (PubMed:15790312, PubMed:17035250, PubMed:17255108). Interacts with EFEMP2 with moderate affinity (PubMed:16478991).TISSUE SPECIFICITY Expressed within the outer myometrial smooth muscle and throughout the arteriolar tree of uterus (at protein level). Also expressed in the large arteries, lung and skin.PTM Elastin is formed through the cross-linking of its soluble precursor tropoelastin. Cross-linking is initiated through the action of lysyl oxidase on exposed lysines to form allysine. Subsequent spontaneous condensation reactions with other allysine or unmodified lysine residues result in various bi-, tri-, and tetrafunctional cross-links. The most abundant cross-links in mature elastin fibers are lysinonorleucine, allysine aldol, desmosine, and isodesmosine.PTM Hydroxylation on proline residues within the sequence motif, GXPG, is most likely 4-hydroxy as this fits the requirement for 4-hydroxylation in vertebrates.DISEASE ELN is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of ELN may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease (PubMed:8812460).SIMILARITY Belongs to the elastin family.UniProtP1550227EQUAL786EQUALReactome Database ID Release 761454880Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1454880ReactomeR-HSA-14548801Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1454880.110Reactome Database ID Release 762161342Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161342ReactomeR-HSA-21613421Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161342.1Fibrillins:MFAP2,MFAP5:Tropoelastin aggregateReactome DB_ID: 2161254111Reactome Database ID Release 762161254Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161254ReactomeR-HSA-21612541Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161254.1Reactome Database ID Release 762129353Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2129353ReactomeR-HSA-21293532Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2129353.219167375Pubmed2009DANCE/fibulin-5 promotes elastic fiber formation in a tropoelastin isoform-dependent mannerNonaka, RisaOnoue, SatoshiWachi, HiroshiSato, FumiakiUrban, ZsoltStarcher, Barry CSeyama, YoshiyukiClin. Biochem. 42:713-218458869Pubmed1993Emilin, a component of elastic fibers preferentially located at the elastin-microfibrils interfaceBressan, GMDaga-Gordini, DColombatti, ACastellani, IMarigo, VVolpin, DJ Cell Biol 121:201-1217459412Pubmed2007Distinct steps of cross-linking, self-association, and maturation of tropoelastin are necessary for elastic fiber formationSato, FWachi, HIshida, MNonaka, ROnoue, SUrban, ZStarcher, BCSeyama, YJ Mol Biol 369:841-5118468477Pubmed2009TropoelastinWise, SGWeiss, ASInt J Biochem Cell Biol 41:494-719798595Pubmed2009Fibulin-5, an integrin-binding matricellular protein: its function in development and diseaseYanagisawa, HiromiSchluterman, Marie KBrekken, Rolf AJ Cell Commun Signal 3:337-4714701737Pubmed2004EMILIN-1 deficiency induces elastogenesis and vascular cell defectsZanetti, MiriamBraghetta, PaolaSabatelli, PatriziaMura, IsabellaDoliana, RobertoColombatti, AlfonsoVolpin, DinoBonaldo, PaoloBressan, Giorgio MMol. Cell. Biol. 24:638-5011805834Pubmed2002Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivoYanagisawa, HDavis, ECStarcher, BCOuchi, TYanagisawa, MRichardson, JAOlson, ENNature 415:168-7116331676Pubmed2006Elastic fiber macro-assembly is a hierarchical, cell motion-mediated processCzirok, AndrasZach, JuliaKozel, Beth AMecham, Robert PDavis, Elaine CRongish, Brenda JJ. Cell. Physiol. 207:97-10616906757Pubmed2006Tropoelastin massively associates during coacervation to form quantized protein spheresClarke, AWArnspang, ECMithieux, SMKorkmaz, EBraet, FWeiss, ASBiochemistry 45:9989-9616042404Pubmed2005Coacervation is promoted by molecular interactions between the PF2 segment of fibrillin-1 and the domain 4 region of tropoelastinClarke, Adam WWise, Steven GCain, Stuart AKielty, Cay MWeiss, Anthony SBiochemistry 44:10271-8117130242Pubmed2007Molecular analysis of fibulin-5 function during de novo synthesis of elastic fibersZheng, QianDavis, Elaine CRichardson, James AStarcher, Barry CLi, TiansenGerard, RDYanagisawa, HiromiMol. Cell. Biol. 27:1083-9517371835Pubmed2007Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivoHirai, MaretoshiOhbayashi, TetsuyaHoriguchi, MasahitoOkawa, KHagiwara, AkariChien, Kenneth RKita, ToruNakamura, TomoyukiJ. Cell Biol. 176:1061-7115790312Pubmed2005Fibulin-5 interacts with fibrillin-1 molecules and microfibrilsFreeman, Lyle JLomas, AmandaHodson, NigelSherratt, Michael JMellody, Kieran TWeiss, Anthony SShuttleworth, AdrianKielty, Cay MBiochem. J. 388:1-5