extracellularmatrix-111109073434-phpapp01

8/19/2019 extracellularmatrix-111109073434-phpapp01

1/28

EXTRACELLULARMATRIX

Mrs. OFELIA SOLANO SALUDAR

Department of Natural SciencesUniversity of St. La Salle

acolo! City


2/28

Many animal cells are intrinsically lin"e! to ot#ercells an! to t#e e$tracellular matri$ %ECM&.

Cell surface molecules 'in! to ot#er cells( or to

ot#er components of t#e ECM. T#ey also play arole in mutual reco)nition of similar cell types.

one an! cartila)e are mostly ECM plus a very fe*cells. Connective tissue t#at surroun!s )lan!s an!

'loo! vessels( is a )elatinous matri$ containin)many +'ro'last cells.


3/28

T#e ECM contains , classes of molecules- structural proteins %colla)ens an! elastins& proteinpolysacc#ari!e comple$es to em'e! t#e

structuralproteins

%proteo)lycans& a!#esive

)lycoproteins to attac# cellsto matri$

%+'ronectins

an! laminins&.


4/28

PROTEOGLYCANS

1.PROTEOGLYCANS are compose! of a core protein to *#ic#)lycosaminolycans %GAGs& are attac#e!. /A/s consist ofrepeatin) !isacc#ari!e su'units. 0ne of t#e t*o su)ars in t#e !isacc#ari!e is often an amino

su)ar %Nacetyl)lucosamine or Nacetyl)alactosamine1 usually*it# an attac#e! sulfate )roup& an! t#e ot#er is a su)ar or su)araci! %)alactose or )lucuronate&.

Chondroitin sulfate, keratan sulfate, heparan sulfate an!

haluronate are t#e most common /A/s.


5/28

Eac# of t#e four classes of /A/s isforme! 'y polymeri2ation of monomer

units into repeats of a particular!isacc#ari!e an! su'se3uent

mo!i+cations( inclu!in) a!!ition ofsulfate )roups an! inversion of t#ecar'o$yl )roup on car'on 4 of D

)lucuronic aci! to yiel! Li!uronic aci!.

!eparin is )enerate! 'y#ypersulfation of #eparan sulfate(

*#ereas haluronan is unsulfate!. T#e s3ui))ly lines represent

covalent 'on!s t#at are oriente!eit#er a'ove %D)lucuronic aci!& or

'elo*%Li!uronic aci!& t#e rin).


6/28

Most /A/s in t#e ECM are 'oun! to proteinsto form proteo)lycans or mucoproteins.

Numerous /A/s %5677 per molecule(avera)e len)t# of 877 monosacc#ari!eunits& are attac#e! to a core protein an!!i9erent "in!s of proteo)lycans can 'e

ma!e 'y varyin) t#e com'ination of coreproteins an! /A/s.

:roteo)lycans %M; of< 5 million& can 'ein!ivi!ual or attac#e! to lon) #yaluronate

molecules to form comple$es %as incartila)e&.

T#ey can 'e em'e!!e! in t#e plasmamem'rane or covalently lin"e! tomem'rane p#osp#olipi!s or 'oun! to


7/28

:roteo)lycans an! colla)en may 'in! toreceptor proteins %often inte)rins& *#ic# arereinforce! 'y a!#esive )lycoproteins( suc# as

+'ronectins an! laminins( to anc#or cells to t#eECM.

/A/s in CT are #i)#ly sulfate! *#ic# attracts*ater of #y!ration. T#ey trap *ater %up to 47$

t#eir *ei)#t& to act as e$tracellular spon)esresistant to p#ysical forces in cartila)e an!

=oints. If >ui! is in=ecte! into CT( it remains locali2e!(

*alle! o9 'y a viscous )roun! su'stance. T#isproperty acts as 'arrier to t#e sprea! of'acteria t#at )ains access to t#e tissues.

Some 'acteria secrete haluronidase

%Staphylo/ Strepto/ Pneumococci&( an!"olla#enase %Clostridium perfringens& t#at


8/28

E$E%A is a con!ition c#aracteri2e! 'yaccumulation of e$cess tissue >ui!.


9/28

E!ema accompanies pat#olo)ical con!itions t#atcause-Increase! #y!rostatic pressure

in capillaries 'y o'structin)venous 'loo! >o*

%e.).con)estive #eart failure&

Decrease! colloi! osmotic pressure in t#e 'loo!cause! 'y lac" of 'loo! proteins %e.).starvation&

Increase! #y!rostatic pressure in t#e tissue

cause! 'y 'loc"a)e of lymp#atic!raina)e 'y parasites or tumor cellsIncrease! colloi! osmotic pressure in

t#e tissue cause! 'y e$cessiveaccumulation of /A/s in

t#e matri$.


10/28

COLLAG

EN

(

)*ER

S


11/28

:rincipal pro!ucers of colla)en +'ers are +rolasts- epit#elial an! smoot# muscle cells also secrete t#eiro*n typeI@ colla)en.

Most numerous CT matri$( runnin) in all !irections in a*avy course1 !ull an! opa3ue in appearance.

i'ers 'un!le! to)et#er 'ranc# an! anastomose1in!ivi!ual +'ers !o not 'ranc#.

;it# t#e EM( unit +'rils of colla)en s#o* perio!ic cross

striations every B nm of t#eir len)t#.


12/28


13/28

%a& In ten!ons( type I+'rils are all oriente! in t#e

!irection of t#e stressapplie! to t#e ten!on.

:roteo)lycans an! type @Icolla)en 'in! noncovalently

to +'rils( coatin) t#esurface. T#e micro+'rils of

type @I colla)en( *#ic#contain )lo'ular an! triple

#elical se)ments( 'in! totype I+'rils an! lin" t#em to)et#er

into t#ic"er +'ers. %'& Incartila)e( type IX colla)enmolecules are covalently'oun! at re)ular intervals

alon) type II +'rils. Ac#on!roitin sulfate c#ain(covalently lin"e! to t#e 6

type IX c#ains at t#e >e$i'le"in"( pro=ects out*ar! from

t#e +'ril( as !oes t#e

)lo'ular Nterminal re)ion.

Interactions of +'rouscolla)ens *it# non+'rous

+'rilassociate! colla)ens.


14/28


15/28

1.)NTRACELLLAR free polysomes rea!in) colla)enmRNA attac# to t#e rER( an! proto"olla#en orpre"olla#en/c#ains are !eposite! in t#e cisternae. Eac#

c#ain #as a'out 647 amino aci!s1 every ,r! amino aci! is)lycine.

. T#e si)nal pepti!e is clippe! o9. :roline an! lysineresi!ues *it#in t#e c#ains are t#en #y!ro$ylate! in t#eER to form hdro'proline an! hdro'lsine

%unusual amino aci!s present in lar)e amounts incolla)en&.

.Core su)ars %)alactose an! )lucose& attac# to t#e#y!ro$ylysine resi!ues in t#e ER.

.Eac# c#ain is synt#esi2e! *it# an e$tra len)t# ofpepti!es "no*n as re)istration pepti!es( *#ic# ensuret#at t#e appropriate c#ains assem'le in t#eir correctposition in t#e resultin) triple #elical molecule calle!pro"olla#en.

.

urt#er )lycosylation may occur in t#e /ol)i comple$(*#ere procolla)en is pac"a)e! for secretion. /ol)i


16/28

1.E0TRACELLLAR in t#e e$tracellular space(t#e en2yme procolla)en pepti!ase cleaves t#ere)istration pepti!es from procolla)en(convertin) it to tropo"olla#en.

.Cataly2e! 'y lsl o'idase( t#ese 'ecomeali)ne! in sta))ere! fas#ion to form colla)en+'ers( possi'ly un!er t#e control of a!=acent+'erpro!ucin) cells.

. T#e turnover of colla)en is slo*est in ten!ons(fastest in loose CT. Macrop#a)es an!neutrop#ils 'rea" !o*n ol! colla)en( an!replace! 'y +'ro'lasts.

.As #umans a)e( e$tracellular colla)en'ecomes increasin)ly crosslin"e!( turnoverslo*s !o*n in CT.


17/28

Pro#ressie sste&i" s"lerosis e$cessiveaccumulation of colla)en %+'rosis& in almost allor)ans

2eloid local s*ellin) cause! 'y a'normal amountsof colla)en t#at form in scars of s"in

Ehlers/$anlos tpe )3 aorticF intestinal rupture!ue to faulty transcription of colla)en type III

Ehlers/$anlos tpe 3)) increase! articularmotility !ue to !ecrease! procolla)en pepti!aseactivity

S"ur ulceration of )ums( #emorr#a)es !ue tolac" of @it. C( a cofactor for proline #y!ro$ylase

Osteo#enesis i&perfe"ta spontaneous fractures

ecause colla)en synt#esis !epen!s on t#ee$pression of several )enes an! on several

posttranslation events( many #uman !iseases

are associate! *it# faulty colla)en synt#esis.


18/28

orm )entle curves or spirals at t#eir free en!s

*#en release! from tensionDo not form 'un!les1 in!ivi!ual +'ers 'ranc#an! anastomose to form net*or"s

T#ey can 'e stretc#e! to 547H of t#eir len)t#

*it#out 'rea"in)( 'ut lose t#eir resiliency *it#a!vancin) a)e.Appears yello*is#( #i)#ly refractile(

#omo)enous an! are not ma!e up of +'rillarsu'units t#at are visi'le *it# t#e li)#tmicroscope.

Eac# +'ril is ma!e up of still smaller +'rilsunite! 'y a small amount of )roun! su'stance.

T#ese smaller micro+'rilsJ #ave perio!ic cross'an!in)s.

YELLO4 or ELAST)C ()*ERS


19/28

1.)ntra"ellular micro+'rillar proteins containin)mostly #y!rop#ilic amino aci!s( an! proelastin

%contains lar)e amounts of t#e #y!rop#o'ic aminoaci!s )lycine( proline an! valine( t#us accountin)for elastinKs insolu'ility& are synt#esi2e! on rERan! secrete! separately.

5.E'tra"ellular proelastin molecules polymeri2ee$tracellularly to form elastin c#ains. Lsl o'idases t#en cataly2e t#e conversion of

certain lysine resi!ues of elastin to al!e#y!es( ,of *#ic# con!ense *it# a t# unaltere! lysineresi!ue to form des&osine an! isodes&osine.

T#ese very rare amino aci!s foun! in elastincrosslin" in!ivi!ual c#ains( *#ic# t#en associate*it# numerous micro+'rils to form a 'ranc#in)

an! anastomosin) net*or" of elastic +'ers.

Snthesis and Asse&l of Elastin6


20/28

i'ers are not 'ranc#e!( an! are not so *avy ast#e colla)enous +'ers *#en release! from tension.

T#ey are c#emically i!entical to colla)en( #encet#ese +'ers are consi!ere! as precursors of type Ian! III colla)en1 #o*ever( t#ey are t#inner an!form !elicate net*or"s instea! of t#ic" 'un!les

C#emical c#aracteristics s#o* aGnity to silver%'lac"& stains( #ence ar)yrop#yl1 !o not yiel!)elatin on 'oilin)1 not easily !issolve! 'y !iluteaci!s an! al"ali1 not so easily !i)este! 'y )astric

=uice1 not so resistant to solutions of al"alinepancreatic =uice. Distri'ution a'un!ant in re)ions aroun! 'loo!

vessels( muscle +'ers( fat cells( 'asementmem'rane of epit#elia( en!oneurium( lymp#oi!

or)ans an! re! 'one marro*.

ARGYROP!YL or RET)CLAR()*ERS


21/28

/lycoproteins are)lo'ular proteins to*#ic# s#orter( 'ranc#e!oli)osacc#ari!e c#ainsare covalently 'oun!.

T#ese socalle! a!#esion)lycoproteins me!iate

attac#ment of cells tot#eir matri$( in>uencet#e state of!i9erentiation of cells(

an! or)ani2ation of t#eircytos"eleton. E$amples are +'ronectin(

laminin( t#rom'ospon!in(c#on!ronectin an!

+'rillin.

/LC0:R0TEINS


22/28

()*RONECT)NS( a family ofclosely relate! )lycoproteins( aresolu'le in 'o!y >ui!s %'loo!&(insolu'le in t#e ECM an! partially

solu'le at t#e cell surface. T#e +'ronectins 'in! cells to t#e

matri$ an! )ui!e cellularmovement.

T#e R/D %ar)inine)lycine

aspartate& se3uence 'in!s to t#einte)rin +'ronectin receptor.

T#e +'ronectins 'in! cells to t#eECM 'y 'ri!)in) cellsurfacereceptors to t#e ECM.

T#e intracellular cytos"eleton *illali)n *it# t#e e$tracellular+'ronectin to !etemine cell s#ape.

In many "in!s of cancer( cellsuna'le to ma"e +'ronectins looses#ape an! !etac# from t#e ECM to'ecome mali)nant.


23/28

Durin) cell movement %as!urin) em'ryo)enesis&(

pat#*ays of +'ronectins)ui!e cells to t#eir!estinations.

Solu'le plasma

+'ronectin promotes'loo! clottin) 'y !irect'in!in) of +'rin.

i'ronectins )ui!eimmune cells to *oun!e!areas an! t#us promote*oun! #ealin).


24/28

LA%)N)NS 'in!cells to t#e 'asallamina of epit#elialan! connectivetissues( an! to t#eirsurroun!in) musclecells( fat cells( an!

Sc#*ann cells. T#e 'asal lamina

serves as astructural support

for tissues an! as apermea'ility 'arrierto re)ulatemovement of 'ot#

cell an! molecules.


25/28

Laminin is a verylar)e protein

comprise! of t#ree

proteins t#at form across. T#e !omains oflaminin 'in! type I@colla)en( #eparin(

#eparin sulfate(entactin an! lamininreceptor proteins in

overlyin) cells toallo* 'ri!)in)

'et*een t#e cells an!t#e ECM. Pro#eria

%early onset of a)in)&(is possi'ly !ue to a

!efective laminin.


26/28


27/28

T#e D/C comprises ,su'comple$es- dstro#l"an,sar"o#l"an7 sar"ospan of

inte)ral mem'rane proteins1 an!t#e cytosolic a!apter comprisin)

dstrophin( ot#er a!apterproteins( an! si)nalin) molecules.

T#rou)# its 0lin"e! su)ars(!ystro)lycan 'in!s to components

of t#e 'asal lamina( suc# aslaminin. Dystrop#in t#e protein!efective in Duc#enne muscular

!ystrop#y( lin"s !ystro)lycan to t#eactin cytos"eleton( an! !ystro'revinlin"s !ystrop#in to t#e sarco)lycanFsarcospan su'comple$. Nitric o$i!e

synt#ase %N0S& pro!uces nitrico$i!e( a )aseous si)nalin)

molecule( an! /R6 is a component

of si)nalin) pat#*ays activate! 'ycertain cellsurface receptors.

Mutations in !ystrop#in( ot#er D/Ccomponents( laminin( or en2ymes

t#at a!! t#e 0lin"e! su)ars to!ystro)lycan !isrupt t#e D/C

me!iate! lin" 'et*een t#e e$terior

an! t#e interior of muscle cells an!cause muscular !ystrop#ies.

S"he&ati" &odel of thedstrophin #l"oprotein "o&ple'8$GC9 in skeletal &us"le "ells.

Molecular Connections et*eenECM an! Disease- Muscular

Dystrop#y


28/28

extracellularmatrix-111109073434-phpapp01

Documents