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31
صبا المسیمي
تسنیم الرواضیة
دیاال
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ExtraCellularMatrix(ECM)
*TheECMisaspacethatsurroundsthecellandisoccupiedbyagroupofmoleculesthatfacilitateinteractionsbetweencellsaswellasthesurroundingenvironment.
*Insometissues,theECMisthemajorcomponent,forexampletheconnectivetissues(e.g.,cartilage,boneandtendon),unlikeepithelium,epithelialcellshaveaminimalamountofECMwhichisfoundmostlyinthebasallamina(basementmembrane).
*TypesofECM:
1-basallamina:
-isathinsheetlikestructureuponwhichlayersofepitheliallayersrest
-itseparatesepithelialcellsfromunderlyingconnectivetissue.
-itsupportssheetsofepithelialcells
-itsurroundsmusclecells,adiposecellsandperipheralnerves.
2-Connectivetissue(Bone,Tendon,Cartilage)
-Loosenetworkofproteinsandcarbohydratesunderneathepithelialcelllayerswherefibroblastsaredistributed
DifferenttissueshavedifferentECMcomponentshowever,therearecertaincomponentsthatarefoundinallECMs:
-Proteins:
1-fibrousproteins:”toughfibrousproteinsembeddedinagellikepolysaccharidegroundsubstance”FROMSLIDES
2-adhesionproteins:connectdifferenttypesofmolecules
-polysaccharides:interactwithcoreproteinstoform(proteoglycans=glycosaminoglycans(GAGs)+coreproteins)
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DifferentECMCompositions
A)Bone:
Osteocytessitinlacunaeandarewidelyseparated
MostofthebonetissueisECM.ECMishardenedbydepositionofinorganicmolecules(calciumphosphatecrystals)whichisimportantforthenature,propertiesandfunctionofthebonetissue.
B)Cartilage:
ItsECMisflexiblebecauseitconsistsoflargenumberofproteoglycans,proteoglycansaremainlyofsugarswhicharepolarmoleculesthathavetheabilitytointeractwithwatermolecules,producinggel-likestructurethatallowsthecartilagetoperformitsfunctionasshockabsorbent(cushion).Oneofthemostabundantproteoglycanspresentinthecartilageishyaluronicacid.
C)ConnectiveTissue:
Tendonscontainahighproportionoffibrousproteins(elastic-thefinefibersandcollagen-thethickfibers,theygivethemechanicalstrength).
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Tendonsattachmusclestobonessoitisexposedtobigforcesespeciallyincontractionofthemusclemustbemechanicallystrongandhavesomesortofflexibilityatthesametimebecauseitmustmovewiththemuscle.
Nowlet’stalkindetailsaboutthegeneralcomponentswe’vementionedabove:1)Fibrousproteins:
a)Collagens
-themostabundantproteinpresentinourbodies,it’sastructuralproteinarrangedintriplehelices,it’scomposedofhighlevelsof(Proline13%,hydroxyproline9%andGlycine33%).Bothprolineandlysinegetintohydroxylationprocess,inwhichweaddOHgroup,thismodificationisposttranslational
-Hydroxylysinespecificallyservesasattachmentsiteforsugar,makingitaglycoprotein.Also,therearecrosslinkingprocessesthathappenbetweenHydroxylysineandLysinetoattachcollagenmolecules.
Therearemanytypesofcollagenmolecules
1)Fibrilformingcollagen(type1)
2)Fibrilassociatedcollagen(type9,12)
3)Networkformingcollagen(mostlyinthebasallamina,Type4)
4)Anchoringfibers(associatenetwork-formingcollagentofibril-formingcollagen)
5)Transmembrane(theyparticipateintheinteractionbetweenthecellanditsECM).
Likeanyotherprotein,collagenisencodedbyageneandisgoingtobetranscribedandsynthesizedbyribosomes,interactionbetweenthreepolypeptidechains,toformthebasicunitsofmaturecollagenwhichiscalled(TropoCollagen)thisbasicunitisgoingtoberepeatedmanytimestoformfibrilsandthenfibers.Fibrilsare
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tropocollagensthatarepartiallyoverlappedtodistributethespacesinbetweenthemindifferentregionstoavoidcreatingweakpoints.Associationoffibrilsformstructurescalledfibirswhichareabout10timesthickerthanfibrils.
Nowe'regoingtotalkaboutsomedetails,
Insidethecell,proteinaresynthesizedbyribosomestheygettranslocatedintotheER,wherehydroxylationofprolinehappens
Then,hydroxylysinesareglycosylatedandthen3polypeptidechainsaregoingtointeracttoformastructurecalledprocollagen,thenitisexcretedbyexocytosisandfurthermodificationsaregoingtohappeninsideECMincludingcleavageofthegreenareasthatarenotmadeintoheliceslikepropeptidesbyanenzymecalledpropeptidase,nowthetropocollagenisreadytobeassembledintofibrilsandthenfibers.
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Applications:
1)Scurvy:adiseaserelatedtodeficiencyinvitaminC.VitaminCisessentialinhydroxylationofproline.hydroxylationistheadditionofOHgroupwhichformsthehydrogenbondsinthecollagenmolecule,makingitastrongmolecule,soifthereisnoOHgroup,thecollagenstructurebecomesweakercausinglacerationsinthetissuesthatcontaincollagenlikegums,skin,andbloodvessels.
2)Osteogenesisimperfect:imperfectboneformation,ageneticdiseasewhichisautosomaldominant(onecopyoftheabnormalgeneisenoughtocauseit.CausedbymutationsinseveralcollagentypeslikeCOL1A1andCOL1A2resultingindifferenttypeswithdifferentseverities.
Type1isthemildestformandtype2isthemostsevereandmightcausedeathofthefoetusinthewomb.itcausesdeformitiesintheskeletonlikethecurveshowninthex-ray,weakstructureintheirbones(brittlecanbebrokeneasily).
3)Chondrodysplasia:relatedtocartilageduetomutationsintype2collagen.Cartilageisfoundintheepiphysealplateswheregrowthandthenossificationofthebonehappen.so,abnormalstructureofthecartilageisgoingtoresultindwarfism(thetypeofdwarfismwherethewholebodyisshortbutthefaceisnormal.Itcanalsocausejointproblemsbecauseabnormalquantityorqualityifcartilageinthejoint.
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4)EhlersDanlossyndrome:Causedbymutationsinmorethanonetypeofcollagen(ex:TYPE1,3,5)orinenzymesthatmodifyandassemblecollagen,sotheyaffectthestructureofcollagen.Signsandsymptomsdependontheunderlyingmutation.Someoftheuniquefeaturestheyhaveisthehyperextensibilityoftheirskinandhypermobilityoftheirjoints
b)ELASTIN
ThesecondtypeoffibrousproteinintheECMiselastinwhichformselasticfibers,theyaddelasticityandflexibilitytothetissue,sotheresizeissmallerthancollagen.Theyhavecommonfeatureswithcollagenandsomedifferencesalso.
Comparisonbetweenfeaturesofelastinandcollagen:
1-Theyarerichinlysineandprolinelikecollagen,buttheydon’thaveasmuchhydroxyprolineascollagen.
2-Theydon’thydroxylysinewhichmeansthatthereisnoglycosylationontheirproteins.
Bystudyingtheprimaryfeaturesofelastinthefoundthattheresegmentsintheaminoacidsequencethatgivethepropertiesofelastin(ex:hydrophobicstretchesgiveelastinitselasticityandalanine-lysinerichstretchescontributetothecrosslinkingofmoleculestogether.
Synthesisandassembly:
1-Synthesisstartsinribosomes
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2-TheyentertheERmodificationstartsincludinghydroxylationofproteins
3-stilltheelastinhaspropeptidesthataregoingtobecutintheECMusingaproteincalledtropoelastin,itcutstheextrapart
4-Assembly(association)oftropoelastinwithmicrofibrillarproteins(othertypeofproteins)toformastructurethatisthencrosslinkedtoformthestructureofelastin.
Thereisadifferencebetweenelastinandcollagenformationespeciallyintheend(inassembly):thereismicrofibrillarproteinsandtheirstructureisgoingtogetassembledinadifferentwaythancollagen.
Application
Elastinpresenceinthewallsofarteriestunica(layer)internaisimportantingivingflexibilitytothearteriesandmakingthemreturnbacktotheirnormalpositionaftereatingsaltwhichincreasestensioninthearterialwallsesspeciallythatthearterialwallsarethick.Ifthereisamutationinelastinordeficiencyorabnormalstructurewhathappensisthatsmoothmusclestrytocompensatesotheyconstrictbutbecausetheyarenotelastic,theycannotgetbacktotheirnormalpositioncausingnarrowing,construction,highpressure…..
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Microfibrils
Anelastincoreiscoveredwithasheetofmicrofibrils.Microfibrilsarecomposedofanumberofdistinctglycoproteinsincludingthelargeglycoproteinfibrillin,whichbindstoelastinandisessentialforthe
integrityofelasticfibers.Itispresentinhairandspermtail.
Clinicalapplicationsofdiseasesrelatedtoelastinfiber
1-Marfun’ssyndrome:ageneticdiseasemutationsinfibrillin(themicrofibrillarprotein)causesabnormalstructureofelasticfibersleadingtoruptureofaorta,longextremities,abdomenisretorted.
2-Emphysema(destructivelungdisease)
Mostlycausedbycigarettesmoking,thelunghaslungsacksfilledwithairduringinhalationforgasexchange,thenduringexhalationitbecomesempty.Itisflexible(itexpanselikeaballoon)Ifwehaveanormalstructureofelasticfibersthatmeansthattheylosttheirelasticity,causingdeficiencyinbreathing.ToxinsincigarettesinhibitanenzymecalledAlphaoneantitrypsinonceAlphaoneantitrypsinhaslowactivity,overActivationofanenzymecalledelastasehappenswhichdestructselasticfiberssowelosethatqualityofthelungsacs,EmphysemamightbecausedbyageneticmutationinAlphaoneantitrypsincausingit’sdeficiency.
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Polysaccharides
PolysaccharidearethesecondcomponentoftheECMwearegoingtotalkabout,theyareglycosaminoglycans(GAGs)whicharedisaccharideunitsrepeatedsomanytimestoformapolysaccharidestructure,thedisaccharideiscomposedofmodifiedsugars(oneofthesugarsisaminatedlikeN-AcetylglucoseamineorN-Acetylgalactoseamineandtheothersugariseitheroxidizedwhichmeansthatoneofitsgroupsbecomesacarboxylgroupandthesugarbecomesacidicorsulphatedwhichmeansithasanegativechargefromthenegativesulphategroup.)sothesedisaccharidesarehighlypolar,andhighlychargedtheyattractwatermoleculestothemtheyformgellikestructuresandtheyactascushions(shockabsorbers)
Gagsalwaysassociatewithcoproteinsasaminorcomponenttoformthestructureofproteoglycans.
Therearemanykindsofproteoglycans,somecanbefoundfloatingintheECMandothersarecellsurfaceproteinswitheithertransmembranedomains(syndecans)orGPIanchors(glycipans)interactingwithintegrins.
Examplesonmatrixpolysaccharides
1-Aggrecanandhyalronan:hyalronanisthemajorproteoglycanofcartilageECM.
Agrecaniscomposedofcoreproteinandchondroitinsulphate(hairlikestructure)anditcanaggregatewithhyaluronantomakeahighlypolarwaterattractingstructure.
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2-Perlecan:foundinthebasallaminaspecificallyanditinteractswithothercomponentsoftheECMlikecollagentype4andlaminin,soitcontributesinthestructureofbasallamina.
Matrixadhesionproteins
ThesearethirdcomponentoftheECM.Therefunctionisadhesionbetweenfibrousproteinsandpolysaccharidesexamples:
1- Fibronectin:itisaproteinthatformsdimers,thesedimersarecrosslinkedbydisulphidebridges.theyhaveasiteforbindingproteoglycans,siteforbindingcollagen(afibrousprotein),andsiteforbindingtothecells.
2-Laminin:itconnectsbetweencollagenandperlecan(aproteoglycan)itsshapeislikeacrossmadefrommorethanonechain:alpha,beta1andbeta2chainsareinterwindaroundeachother.Intheareawherethesechainsareinterwind,thereisasiteforcellbinding.Onthestructurethereareothercellbindingsites,collagenbindingsitesentactinbindingsite,andproteoglycanbindingsite.Sotheyhavebindingsitesforfibrousproteins,proteoglycans,aswellascells.
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HowdoestheECMinteractwithcells?
BycellularadhesionsbetweencellandECM(notbetweencells)like:
1-Focaladhesions:formedfromintegrins+talin+vinculin.Connectedtoactinfilament.
2-Hemidesmosomes:formedfromintegrins+plectin(aconnectorproteinthatisconnectedtointermediatefilamentsfromtheinsideandtotheECMfromtheoutside).
INTEGRIN(foundinbothfocaladhesionsandhemidesmosomes)iscomposedoftwoproteins:alphaandbeta,eachproteinhasadifferentbindingsitetothematrixprotein.Integrinhas2confirmations,bindinganddetachment.Whenitisinactive,itisbentandawayfromtheECM.Onceitisactive,itcanbindtotheECMandformfocaladhesions,theseconformationalchangeshappenwhilethecellsmove.Integrinisdeactivatedinthesitewheredetachmentisneededandisactivatedintheleadingedgewherebindingandfocaladhesionformationisneeded.
TypesofECMinteractions
InteractionsintheECMaredividedintotwotypesaccordingtotheirtype:
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1-Homophilicinteractions:interactionbetweentwoproteinsfromthesamekind.
2-Heterophilicinteractions:interactionbetweentwodifferentkindsofprotein.Forexampleintegrinsarefoundinfocal
adhesionsaswellashemidesmosomes;theyinteractwiththeECMortheymightinteractwithagroupofproteinscalledIGsuperfamilyimmunoglobulin.Igsuperfamilyisdifferentthanintegrinsoitisconsideredthetroublethinksoitisconsideredheterophilicinteraction.ImmunoglobulinIGsuperfamilyalsointeractwithintegrinsbuttheydon'tproduceanycellularjunctionsandtheymightmakehomophilicinteractions.Cadherinscanmakehomophilicinteractionsandtheyproduceadherencejunctionsandsomekindsarefoundindesmosomes(theyarecalleddesmosomalcadherins).Thelastoneisselectin,itinteractwithsugarsfoundonglycoproteins.
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Inthefollowingpicture,don’tmemorizetheexamplesonlyknowthatthefirsttwoshowahomophilicinteractionandthesecondtwoshowa
heterophilicinteraction,thelastoneshowsthattheinteractionisnotnecessarilybetweentwomembraneproteins,itcanbebetweenamembraneproteinanfibronectinintheECM.
Nowe'regoingtotalkabouthowselectinsinteractwithcarbohydratesandhowthiswouldhelpusintheextravasationofleukocytesfrombloodvesselstothesiteofinjury(howitgetsoutbetweentheendothelialcellsuntilitreachesthesiteofinjury.)inthepicture:
Bluebloodstream
Pinkendothelialcells(liningofbloodvessels)
Thecirclesaretheleucocytesthataregoingtogetoutofthebloodvessels.
Onthesurfaceoftheleucocytesthereisatypeofselectin,theLselectin
OntheepithelialcellthereareE-selectinsandP-selectins.
*selectinsdon'tinteractwitheachother,interactionhappensbetweenselectinandsugarsofglycoproteins.
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1-InteractionbetweenPandE-selectinandglycoproteinsonthesurfaceofleukocytes.
2-PandE-selectins‘grab’aleukocyteandpullitnearthecellmembrane.
3-Signalingpathwaysareactivatedinsidetheleukocyte,whichwillinduceaccumulationofintegrinsinoneregion,theseintegrinsbindtootherproteinsonthesurfaceofendothelialcellscalledintracellularadhesionmolecules(ICAM),ICAMisapartifIGSF,IGSFinteractwithintegrinsinaheterophilicinteraction.
4-Westartedwithaninteractionbetweenselectinandcarbohydrates,thenintegrinsandIGSF.Nowthattheleukocyteisveryclosetothecellmembrane,itcanbepulledinsidethebloodvesselandallowedtotraveltothesiteofinjury.
GOODLUCK!!!