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Theextracellularmatrix(ECM))
TheECMconsistsofthreemajorclassesofmolecules:

Connectivetissues
Dr.AtifHassanKhirelsied DepartmentofBiochemistry FacultyofMedicine InternationalUniversityofAfrica

1. Structuralproteins:collagenandelastin and fibrillin1. 2. Specializedproteins:e.g.fibronectin,andlaminin. 3. Proteoglycans.

Thestructuralproteins

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Elastin
Elastin confersextensibilityandelasticrecoilintissues.

Elastin
Unlikecollagen,thereisonlyonegenetictypeofelastin.

Elastin ispresentinlargeamountsinlung,largearterial , g bloodvessels,andsomeelasticligaments.

Itissynthesizedasasolublemonomercalled tropoelastin. tropoelastin

Smallerquantitiesofelastin arealsofoundinskin,ear cartilage.

Tropoelastin isnotsynthesizedinapro formwith extensionpeptides.

Elastin
Unlikecollagen,elastin doesnotcontainGlyXY sequences,triplehelicalstructure,orcarbohydrate moieties.

Elastin
Similartocollagen,certainlysyl residuesoftropoelastin are oxidatively deaminated toaldehydes bylysyl oxidase.

Themajorcrosslinksformedinelastin arethedesmosine uniquetoelastin.

Someoftheprolines oftropoelastin arehydroxylated to hydroxyproline butthereisnohydroxylysine.

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Desmosines crosslink
Collagen

MajorDifferencesBetweenCollagenandElastin Elastin
Onegenetictype Notriplehelix;randomcoil conformationspermittingstretching No(GlyXY)nrepeatingstructure ( y ) p g Nohydroxylysine Nocarbohydrate

Manydifferentgenetictypes Triplehelix ( y (GlyXY)nrepeatingstructure ) p g Presenceofhydroxylysine Carbohydratecontaining

Desmosines,resultfromthecondensationofthreeofthese lysinederivedaldehydes withanunmodifiedlysinetoforma tetrafunctional crosslink

Intramolecular aldol crosslinks Intramolecular desmosine crosslinks Presenceofextension peptidesduringbiosynthesis Noextensionpeptidespresentduring biosynthesis

Fibrilin1
Isalargeglycoprotein. Itisastructuralcomponentofmicrofibrils inmany tissues(lens,periosteum,aorta). Issecretedbyfibroblastsandbecomesincorporatedinto theinsolublemicrofibrils. MutationsareassociatedwithMarfan syndrome.

Marfansyndrome

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Fibronectin (FN)
Isamajorglycoproteinoftheextracellularmatrix Isalsofoundinasolubleforminplasma. Isinvolvedinmanycellularprocesses,includingtissue repair,embryogenesis,bloodclotting,andcell migration/adhesion.

Thespecializedproteins

Fibronectin (FN)
Fibronectin existsintwomainforms: 1. Insolubleglycoproteindimer thatservesasalinker intheECM(extracellularmatrix),producedby variouscellse.g.,fibroblasts,chondrocytes, endothelialcells,macrophagesandepithelialcells. 2. Solubledisulphidelinkeddimer foundintheplasma (plasmaFN),synthesizedbyhepatocytes.

Fibronectin
Theroleoffibronectins istoattachcellstoavarietyof extracellularmatrices.

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Fibronectin
Fibronectin containsanArgGlyAsp(RGD)sequencethat bindstotheintegrin receptors. TheRGDsequenceissharedbyanumberofother proteinsintheECMthatbindtointegrins presentincell surfaces.

Laminins
Thelaminins areafamilyofglycoproteins foundinthe basallamina. Thelaminins areanimportantforcelldifferentiation, migration,adhesion. migration adhesion Laminins aretrimeric proteinsthatcontainanchain,a chain,andachainlinkedtogethertoforman elongatedcruciformshape..

Laminin

Theproteoglycans

IthaspotentialbindingsitesfortypeIVcollagen,heparin,and integrins oncellsurfaces.

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Proteoglycans
Proteoglycansareproteinsthatcontaincovalentlylinked glycosaminoglycans. Thebasicproteoglycan unitconsistsofa"coreprotein" withoneormorecovalentlyattachedglycosaminoglycan (GAG)chain.

Schematicrepresentationoftheproteoglycan aggrecan.

Proteoglycans
Atleast30typeshavebeencharacterizedandgiven namessuchassyndecan,betaglycan,serglycin,perlecan, aggrecan,versican,decorin,biglycan,andfibromodulin. Theyvaryintissuedistribution,natureofthecore protein,attachedglycosaminoglycans,andfunction.

Thefunctionofproteoglycans
1. Bindwaterandformhydratedmatrices. 2. Provideascaffoldforepithelialcellmigration,proliferation, anddifferentiation. 3. Regulatevariousbiologicalactivitiessuchascoagulation, hostdefense,andwoundrepair.

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Thefunctionofproteoglycans
4. Bindcytokines,chemokines,growthfactors,and morphogens,protectingthemagainstproteolysis. 5. Actasreceptorsforproteasesandproteaseinhibitors regulatingtheirspatialdistributionandactivity. l ti th i ti l di t ib ti d ti it 6. Membraneproteoglycanscanactasendocytic receptors forclearanceofboundligands.

Glycosaminoglycans

Glycosaminoglycans
AGAGisanunbranched polysaccharidemadeupof repeatingdisaccharides. Onecomponentofthedisaccharideisalwaysan g , g aminosugar,eitherDglucosamineorD galactosamine.

Glycosaminoglycans
Theothercomponent(exceptinthecaseofkeratan sulfate)isauronic acid,eitherLglucuronic acid (GlcUA)orits5epimer,Liduronic acid(IdUA).

dGlucuronate

liduronate

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Glycosaminoglycans
Thereareatleastsevenglycosaminoglycans: 1. Hyaluronic acid, 2. chondroitin sulfate, 3. keratan sulfatesI 4. keratan lf t II 4 k t sulfatesII 5. heparin, 6. heparan sulfate, 7. anddermatan sulfate.

Glycosaminoglycans (GAGs):
Withtheexceptionofhyaluronic acid,alltheGAGs containsulfategroups,eitherasOestersorasNsulfate (inheparinandheparan sulfate).

Thefunctionsofglycosaminoglycans (GAGs):
Hyaluronic acidisespeciallyhighinconcentrationin embryonictissuesandisthoughttoplayanimportantrole inpermittingcellmigrationduringmorphogenesisand woundRepair.

Thefunctionsofglycosaminoglycans (GAGs):
Chondroitin sulfatesarelocatedatsitesofcalcificationin endochondral boneandincartilage.

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Thefunctionsofglycosaminoglycans (GAGs):
keratan sulfateIand dermatan sulfatearepresentinthe cornea,andplayacriticalroleincornealtransparency. Thepresenceofdermatan sulfateinthescleramayalso playaroleinmaintainingtheoverallshapeoftheeye. Keratan sulfateIisalsopresentincartilage.

Thefunctionsofglycosaminoglycans (GAGs):
Heparinisanimportantanticoagulant. ItbindswithfactorsIXandXI,butitsmostimportant interactioniswithplasmaantithrombin. H Heparincanalsobindspecificallytolipoproteinlipase i l bi d ifi ll li i li presentincapillarywalls,causingareleaseofthisenzyme intothecirculation.

Thefunctionsofglycosaminoglycans (GAGs):
Heparans havelesssulfategroupsthanheparins
Heparan sulfate areassociatedwiththeplasma membraneofcells,withtheircoreproteinsspanningthe membrane. Theyactasreceptorsandmayalsoparticipateinthe mediationofcellgrowthandcellcellcommunication.

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