Connectivetissues

Dr.AtifHassanKhirelsied DepartmentofBiochemistry FacultyofMedicine InternationalUniversityofAfrica

Theextracellularmatrix(ECM)) The extracellular matrix (ECM))

TheECMconsistsofthreemajorclassesofmolecules: The ECM consists of three major classes of molecules: 1. Structuralproteins:collagenandelastin and fibrillin1. 2. Specializedproteins:e.g.fibronectin,andlaminin. 3. Proteoglycans. gy

Thestructuralproteins

Elastin
Elastin confersextensibilityandelasticrecoilintissues. y

Elastin ispresentinlargeamountsinlung,largearterial , g bloodvessels,andsomeelasticligaments.

Smallerquantitiesofelastin arealsofoundinskin,ear g cartilage.

Elastin
Unlikecollagen,thereisonlyonegenetictypeofelastin. g , y g yp

Itissynthesizedasasolublemonomercalled tropoelastin. tropoelastin

Tropoelastin isnotsynthesizedinapro formwith extensionpeptides. extension peptides

Elastin
Unlikecollagen,elastin doesnotcontainGlyXY sequences,triplehelicalstructure,orcarbohydrate t i l h li l t t b h d t moieties.

Someoftheprolines oftropoelastin arehydroxylated to y yp y yy hydroxyproline butthereisnohydroxylysine.

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

Themajorcrosslinksformedinelastin arethedesmosine q uniquetoelastin.

Desmosines crosslink

Desmosines,resultfromthecondensationofthreeofthese lysinederivedaldehydes withanunmodifiedlysinetoforma tetrafunctional crosslink t t f ti l li k

MajorDifferencesBetweenCollagenandElastin Collagen
Manydifferentgenetictypes Triplehelix Triple helix ( y (GlyXY)nrepeatingstructure ) p g Presenceofhydroxylysine Carbohydratecontaining

Elastin
Onegenetictype Notriplehelix;randomcoil No triple helix; random coil conformationspermittingstretching No(GlyXY)nrepeatingstructure ( y ) p g Nohydroxylysine Nocarbohydrate

Intramolecular aldol crosslinks I t I t l l ld l li k Intramolecular d l l desmosine crosslinks i li k Presenceofextension peptidesduringbiosynthesis Noextensionpeptidespresentduring p p p g biosynthesis

Fibrilin 1 Fibrilin1
Isalargeglycoprotein. Is a large glycoprotein Itisastructuralcomponentofmicrofibrils inmany It is a structural component of microfibrils in many tissues(lens,periosteum,aorta). Issecretedbyfibroblastsandbecomesincorporatedinto theinsolublemicrofibrils. MutationsareassociatedwithMarfan syndrome.

Marfansyndrome

Thespecializedproteins

Fibronectin (FN) (FN)

Isamajorglycoproteinoftheextracellularmatrix Is a major glycoprotein of the extracellular matrix Isalsofoundinasolubleforminplasma. Is also found in a soluble form in plasma. Isinvolvedinmanycellularprocesses,includingtissue repair,embryogenesis,bloodclotting,andcell migration/adhesion.

Fibronectin (FN) (FN)

Fibronectin exists in two main forms: existsintwomainforms: 1. Insoluble glycoprotein dimer that serves as a linker Insolubleglycoproteindimer thatservesasalinker intheECM(extracellularmatrix),producedby variouscellse.g.,fibroblasts,chondrocytes, endothelialcells,macrophagesandepithelialcells. 2. Solubledisulphidelinkeddimer foundintheplasma (plasmaFN),synthesizedbyhepatocytes.

Fibronectin
Theroleoffibronectins istoattachcellstoavarietyof extracellularmatrices.

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

Laminins
Thelaminins areafamilyofglycoproteins foundinthe basallamina. Thelaminins areanimportantforcelldifferentiation, migration,adhesion. migration adhesion Laminins are trimeric proteins that contain an chain a aretrimeric proteinsthatcontainanchain,a chain,andachainlinkedtogethertoforman elongatedcruciformshape.. elongated cruciform shape..

Laminin

IthaspotentialbindingsitesfortypeIVcollagen,heparin,and It has potential binding sites for type IV collagen, heparin, and integrins oncellsurfaces.

Theproteoglycans

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

Schematicrepresentationoftheproteoglycan aggrecan.

Proteoglycans
Atleast30typeshavebeencharacterizedandgiven namessuchassyndecan,betaglycan,serglycin,perlecan, aggrecan,versican,decorin,biglycan,andfibromodulin. i d i bi l d fib d li Theyvaryintissuedistribution,natureofthecore protein,attachedglycosaminoglycans,andfunction.

Thefunctionofproteoglycans p gy
1. Bindwaterandformhydratedmatrices. 1 Bi d df h d d i 2. Provideascaffoldforepithelialcellmigration,proliferation, anddifferentiation. 3. Regulatevariousbiologicalactivitiessuchascoagulation, hostdefense,andwoundrepair.

Thefunctionofproteoglycans p gy
4. Bindcytokines,chemokines,growthfactors,and 4 Bi d ki h ki hf d 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 aminosugar,eitherDglucosamineorD g , g galactosamine.

Glycosaminoglycans
Theothercomponent(exceptinthecaseofkeratan sulfate)isauronic acid,eitherLglucuronic acid lf t ) i i id ith L l i id (GlcUA)orits5epimer,Liduronic acid(IdUA).

dGlucuronate

liduronate

Glycosaminoglycans
Thereareatleastsevenglycosaminoglycans: e e a e at east se e g ycosa og yca s 1. Hyaluronic acid, 2. 2 chondroitin sulfate 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). (i h i dh lf t )

Thefunctionsofglycosaminoglycans (GAGs):
Hyaluronic acidisespeciallyhighinconcentrationin embryonictissuesandisthoughttoplayanimportantrole inpermittingcellmigrationduringmorphogenesisand woundRepair.

Thefunctionsofglycosaminoglycans (GAGs):
Chondroitin sulfatesarelocatedatsitesofcalcificationin endochondral boneandincartilage.

Thefunctionsofglycosaminoglycans (GAGs):
keratan sulfateIand dermatan sulfatearepresentinthe cornea,andplayacriticalroleincornealtransparency. cornea and play a critical role in corneal transparency The presence of dermatan sulfate in the sclera may also Thepresenceofdermatan sulfateinthescleramayalso playaroleinmaintainingtheoverallshapeoftheeye. Keratan sulfateIisalsopresentincartilage.

Thefunctionsofglycosaminoglycans (GAGs):
Heparinisanimportantanticoagulant. ItbindswithfactorsIXandXI,butitsmostimportant interactioniswithplasmaantithrombin. interaction is with plasma antithrombin H Heparincanalsobindspecificallytolipoproteinlipase i l bi d ifi ll li i li presentincapillarywalls,causingareleaseofthisenzyme intothecirculation. into the circulation

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

Thanks