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Lecture 11 Endomembrane System
Cell Biology (ZOOLOGY 570)
University of Wisconsin-Madison
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Cytoplasmic Endomembrane System Theor gane l l esoft heendomembr anes ys t em ( Endopl as mi cRe t i c ul um,Gol gic ompl e x,Endos ome s , Ly s os o me s ,& Vac uol e s )f or msadynami c& i nt e gr at edne t wor ki nwhi c hmat er i al sar es hut t l edbac k& f or t hf r om onepar toft hec e l lt oano t her . Mat er i al sar es hut t l edbe t weenor gane l l es ;e . g r om t heGol gi c ompl e xt ot he pl as ma membr ane i ns mal l , membr aneboundedt r ans por tve s i c l e s .Tr ans por tves i c l esbudsofff r o ma donor membr ane and mo ves t hr ough t he c yt opl as m i na di r ec t edmanner ,of t en pul l edbymo t orpr o t ei nst hatmo ves on t r ac ksf o r med by mi c r o t ubul es& mi c r ofil ament so ft he c yt os ke l e t on t hes e ves i c l es r e ac ht hei r des t i nat i on, t he yf us e wi t ht he ac c ept or membr ane c ompar t ment & r e l eas et heves i c ul arc ont ent s . Biosynthetic Pathway A bi o s y nt he t i cpat hwayi sapat hwayi nwhi c hpr o t ei ns ar es ynt hes i z edi nt heendopl as mi cr e t i c ul um,modi fied dur i ng pas s age t hr ough t he Gol gi c ompl e x, and t r ans por t ed f r om t he Gol gi c ompl e x t o var i ous des t i nat i ons ,s uc h as l ys o s omes ,pl as ma membr ane , pl ant vac uol es e t c . Bi os ynt he t i c pat hway i s al s o r e f er r edast hes e c r e t or ypat hwaybec aus emo s tpr o t ei ns s ynt hes i z ed i nt heER ar ede s t i ned t obedi s c har ge d ( s e c r e t e d)f r om t hec e l l . Sec r e t or y ac t i vi t i es o ft he c e l lar e di vi ded i nt ot wo t ypes : ( i . ) Cons t i t ut i ve Se c r e t i on: Dur i ng c ons t i t ut i ve s ec r e t i on,mat er i al sar et r ans por t edi ns e c r e t or y ves i c l es f r om t hei rs i t es of s ynt hes i s and di s c har ged i nt ot he e xt r ac e l l ul ar s pac ei na c ont i nual manner . Mo s t c e l l s engage i n c ons t i t ut i ve s ec r e t i on. I tc ont r i but e st ot he f or mat i on o fe xt r ac e l l ul ar mat r i x and t he pl as mame mbr ane . ( i i . ) Re gul at e dSe c r e t i on:Dur i ngr e gul at eds e c r e t i on,mat er i al sar es t or edasme mbr anebound pac kagesanddi s c har gedonl yi nr es pons et oanappr opr i at emembr anes t i mul us .I toc c ur s , i nendoc r i nec e l l st hatr e l e as eshor mones ,i npanc r eat i cac i narc e l l st hatr e l e as esdi ges t i ve enz ymes ,andi n ner vec e l l st hatr e l eas edneur o t r ans mi t t e r s .Mat er i al si nt hes ec e l l sar e s t or edi nl ar ge ,membr anebounds ec r e t or ygr anul e s . Pr o t e i ns ,l i pi ds ,andc ompl e xpol y s ac c har i de sar et r ans por t e dt hr oug ht hec e l lal ongt hebi o s y nt he t i c ors e c r e t or ypat hway .I ns e c r e t or ypat hway ,mat e r i al smo veouto ft hec e l l . Endocytic Pathway I nendoc yt i cpat hway ,mat er i al smo vef r om t heout ers ur f ac eoft hec e l lt oc ompar t ment s ,s uc has endos omes& l ys o s omes ,l oc at edwi t hi nt hec yt opl as m. Endoplasmic Reticulum (ER) TheER c ompr i s esane t wor kofmembr anest hatpene t r at esmuc hoft hec yt opl as m i st hought t obee vol vedf r om i nvagi nat i onso ft hepl as mamembr ane . ER membr ane s epar at es t he l umen ( an e xt e ns i ve s pac e )enc l os ed wi t hi nt he ER f r o m t he s ur r oundi ngc yt os ol .Thec ompos i t i onofl umi nals pac ei sdi ffer entf r om t hes ur r oundi ngc yt os ol i c s pac e . TheER i sdi vi dedi nt ot wos ubc ompar t ment s ,t heRo ughEndopl as mi cRe t i c ul um ( RER)andt he Smoo t hEndopl as mi cRe t i c ul um ( SER) .TheRER i sdefinedbyt hepr es enc eofr i bos omesboundt o i t sc yt os ol i cs ur f ac e ,wher e ast heSERl ac ksas s oc i at edr i bos ome s .RERi sc ompos edofane t wor kof flat t ened s ac s( c i s t e r nae )& i sc ont i nuous wi t h out er me mbr ane of t he nuc l e ar e nve l ope . Membr anesofSER ar ehi ghl yc ur ved& t ubul arf o r mi ngani nt er c onnec t i ngs ys t em ofpi pe l i nes t r aver s i ngt hr ought hec yt opl as m. Func t i onsofSER Synt hes i sofs t er oi dhor monesi nt heendoc r i nec e l l soft hegonadandadr enalc or t e x. De t o xi fic at i on i nt hel i verofawi devar i e t yofor gani cc ompounds ,i nc l udi ngbar bi t ur at es& e t hanol ,who s ec hr oni cus ec anl e adt ot hepr ol i f er at i ono ft heSER i nl i verc e l l s .De t o xi fic at i on i sc ar r i ed out by c o l l ec t i on o fo xygent r ans f er r i ng e nz ymes ( o x y ge nas e s ) ,i nc l udi ng t he c yt oc hr ome sP450f ami l y. Seques t er sc al c i um i onswi t hi nt hec yt opl as m ofc e l l s .Re gul at edr e l eas eo fCa2+ f r om t heSER ofs ke l e t al& c ar di acmus c l ec e l l st r i gger sc ont r ac t i on. Func t i onsofRER TheRER s er vesast hes t ar t i ngpo i ntf orbi os ynt he t i cpat hway .I ti st hes i t ef ors ynt hes i sof pr o t ei ns ,c ar bohydr at ec hai ns ,and phos phol i pi ds t hat j our ne yt hr ough t he me mbr anous c ompar t ment so ft hec e l l . Appr o xi mat e l yonet hi r do ft hepr o t ei nsenc odedbyamammal i angenomear es ynt hes i z edon r i bos omesat t ac hedt ot hec yt os ol i cs ur f ac eo ft heRER ti nc l udes :s ec r e t edpr o t ei ns ,i nt e gr al membr anepr o t e i ns& s ol ubl epr o t e i nsoft heendomembr anes ys t em. Ot herpol ypept i desar es ynt hes i z edon“ f r ee”r i bos o mes ,i . e .r i bos omesno tat t ac hedt oRER. Onc et he SRPr i bos ome nas c e ntc hai nc ompl e xbi ndst ot heERmembr ane ,t heSRPi sr e l e as ed f r om i t sERr ec ept or ,t her i bos o mebec omesat t ac hedt ot hec yt os ol i cendoft heTr ans l o c on hydr ol y s i sofGTP bound t oSRP & SRP Re c e pt ort oGDP t r i gge r st her e l e as eoft hes i gnal s e que nc ebyt heSRP & i t si ns e r t i on i nt ot heTr ans l oc on n GDP bound s t at e ,SRP hasl o w affini t yf orSRPRe c e pt o r . The s i gnals equenc e oft he nas c entpo l ypept i de i st hen i ns er t ed i nt ot he nar r o w aqueous c hanne lof t he t r ans l oc on,di s pl ac i ng t he pl ug ( Bi P) f r om t he c hanne l& openi ng t he pas s age wayandt her e byal l o wi ngt her emai nderoft hepo l ypept i det ot r ans l oc at et hr ought he hydr ophobi cpor er i ngc ot r ans l at i onal l yi nt ot heRERl umen. Upon t e r mi nat i on of t r ans l at i on & pas s age of t he c ompl e t ed pol ypept i de t hr ough t he t r ans l oc on,t hemembr aneboundr i bos omei sr e l e as edf r om t heRER membr ane& Bi Pc l os e s Tr ans l oc on. Ast henas c entpo l ypept i depas s esi nt ot hel umeno ft heRER,t hes i gnalpept i dei sc l e avedbya pr o t eol yt i ce nz ymes i gnalpept i das e .Car bohydr at esar eaddedt ot henas c entpr o t ei n byt he enz yme ol i gos ac c har r y l t r ans f e r as e .Bo t hs i gnal pe pt i das e & ol i gos ac c har y l t r ans f e r as e ar e i nt e gr alme mbr anepr o t e i nsas s oc i at e dwi t ht het r ans l oc ont hatac tonnas c e ntpr o t e i nast he y e nt e rt heERl ume n. Thepr o t ei nunder goesf ol di ngwi t ht heai dofRER c hape r one s ,s uc hasBi Pt hatr ec o gni z es& bi ndunf ol dedormi s f ol dedpr o t e i nsandhe l pst hem t oat t ai nt hei rnat i ve3Dc onf or mat i on/ s t r uc t ur e . Synt hes i sofI nt e gralMembraneProt ei n( cont ai ni ngs t opt rans f ers equence) I nt e gr almembr anepr o t ei nsar eal s os ynt hes i z edon membr aneboundr i bos omesoft heER. Thes emembr anepr o t ei nsar eal s ot r ans l oc at edi nt ot heRER l umenast he yar es ynt hes i z ed, i . e .c o t r ans l at i onal l y . Unl i kes ol ubl e( s ec r e t or y)pr o t ei nswhi c h pas s esent i r e l yt hr ough t heER me mbr anedur i ng t r ans l oc at i on,i nt e gr alme mbr anepr o t e i nsc ont ai n oneormor ehydr ophobi ct r ans me mbr ane s e gme nt st hatar es hunt e df r om t hec hanne loft heTr ans l oc oni nt ot hel i pi dbi l ay e r . St age s Synt hes i soft hepo l ypept i debe gi nsaf t eramRNA bi ndst oaf r eer i bos o me .Ast hes i gnal s equenc e emer ges f r o m t he r i bos ome ,t he hydr ophobi cs i gnals equenc e/ s t ar tt r ans f e r he l i x)i sr ec o gni z edbyas i gnalr e c o gni t i on par t i c l e( SRP) ,t heSRP bi ndst o s equenc e( bo t ht hes i gnals e quenc eont henas c entpol ypept i de& t her i bos ome ,t empor ar i l yar r e s t i ng f ur t hert r ans l at i on bi ndi ng t or i bos ome al s oi nc r eas e si t saffini t yf orGTP whi l e bi ndi ngo fSRPt os i gnals equenc ei nhi bi t sSRP’ sabi l i t yt ohydr ol yz et heboundGTP. TheboundSRPs er vesasat ag& enabl est heent i r eSRPr i bos ome nas c e ntc hai nc ompl e xt o bi nds pec i fic al l yt ot hec yt os ol i cs ur f ac eoft heERmembr ane . Thebi ndi ngt ot heERoc c ur st hr ought wos equent i ali nt er ac t i ons :oneb/ wt heSRPandt he SRPRe c e pt or ;andt heo t herb/ wt her i bos ome& t heTr ans l o c on. Onc et he SRPr i bos ome nas c e ntc hai nc ompl e xbi ndst ot heER membr ane ,t heSRP i s r e l eas edf r om i t sER r ec ept or ,t her i bos omebec omesat t ac hedt ot hec yt os ol i cendo ft he Tr ans l oc on ol y s i so fGTP bound t oSRP & SRP Re c e pt ort oGDP t r i gge r st he r e l e as eo ft hes i gnals e que nc ebyt heSRP& i t si ns e r t i oni nt ot heTr ans l oc on nGDPbound s t at e ,SRPhasl o w affini t yf orSRPRe c e pt o r . Thes i gnals equenc eo ft henas c entpo l ypept i dei st heni ns er t edi nt ot henar r o w aqueous c hanne loft he t r ans l oc on,di s pl ac i ng t hepl ug ( Bi P)f r om t he c hanne l& openi ng t he pas s age wayandt her e byal l o wi ngt her emai nderoft hepo l ypept i det ot r ans l oc at et hr ough t hehydr ophobi cpor er i ngc o t r ans l at i onal l yi nt ot heRER l umenunt i las t r e t c hofami no nas c entpol ypept i de& t her i bos ome ,t empor ar i l yar r es t i ngf ur t hert r ans l at i on ndi ng t or i bos ome al s oi nc r eas esi t saffini t yf orGTP whi l e bi ndi ng ofSRP t os t ar t t r ans f e r s equenc ei nhi bi t sSRP’ sabi l i t yt ohydr ol yz et heboundGTP. TheboundSRPs er vesasat ag& enabl est heent i r eSRPr i bos ome nas c e ntc hai nc ompl e xt o bi nds pec i fic al l yt ot hec yt os ol i cs ur f ac eoft heERmembr ane . Thebi ndi ngt ot heERoc c ur st hr ought wos equent i ali nt er ac t i ons :oneb/ wt heSRPandt he SRPRe c e pt or ;andt heo t herb/ wt her i bos ome& t heTr ans l o c on. Onc et he SRPr i bos ome nas c e ntc hai nc ompl e xbi ndst ot heER membr ane ,t heSRP i s r e l eas edf r om i t sER r ec ept or ,t her i bos omebec omesat t ac hedt ot hec yt os ol i cendo ft he Tr ans l oc on ol y s i so fGTP bound t oSRP & SRP Re c e pt ort oGDP t r i gge r st he r e l e as eo ft hes t ar t t r ans f e rs e que nc ebyt heSRP& i t si ns e r t i oni nt ot heTr ans l o c on nGDP bounds t at e ,SRPhasl o w affini t yf orSRPRe c e pt or . Thent hes t ar t t r ans f ers e quenc eoft henas c entpol ypept i dei st heni ns er t edi nt ot henar r o w aqueousc hanne loft het r ans l oc on,di s pl ac i ngt hepl ug( Bi P)f r om t hec hanne l& openi ng t he pas s age way and t her e by al l o wi ng t he r emai ndero ft he pol ypept i de t ot r ans l oc at e t hr ough t hehydr ophobi cpor er i ngc o t r ans l at i onal l yi nt ot heRER l umen;e xc eptt heNTer mi nus i s i n t he c yt os ol . Pos i t i ve l yc har ged ami no ac i ds keep t heNTer mi nusaway f r o m t het r ans l o c on. Upon t er mi nat i on oft r ans l at i on, t hemembr aneboundr i bos omei s r e l eas edf r o mt heRERmembr ane & Bi Pc l os e sTr ans l o c on. Me anwhi l e ,t hehydr ophobi cs t ar tt r ans f e rs e que nc emo ve sl at e r al l y outt hr oug h as i de ope ni ngi nt het r ans l oc onandge t si nc or por at e di nt ot hel i pi dbi l ay e r ,f or mi ngape r mane nt t r ans me mbr anepr o t e i n wi t hi t s ’ sNTe r mi nusi nt hec yt o s oland CTe r mi nusi nt heRER l ume n. Synt hes i sofMul t i s panI nt e gralMembraneProt ei ns I n mul t i s pan i nt e gr alme mbr anepr o t e i ns ,oddnumbe r e d 1220hydr ophobi che l i c alami no ac i ds s e r v e as s t ar t t r ans f e rs e que nc e( o r #1 c an be s i gnalpe pt i de s e que nc e )whi l ee ve nnumbe r e d1220hydr ophobi che l i c alami noac i dsal way ss e r v eass t opt r ans f e rs e que nc e .I ft he fir s ts e que nc ei nt hepol ype pt i dei ss t ar t t r ans f e rs e que nc ef ol l o we dbyal t e r nat i ngs t opt r ans f e r& s t ar t t r ans f e rs e que nc e ,t he pol ype pt i de ’ s bo t h NTe r mi nus & CTe r mi nus r e s i de si nt he c yt opl as m ft he fir s ts e que nc ei nt he pol ype pt i de i ss i gnalpe pt i de s e que nc ef ol l o we d by al t e r nat i ngs t opt r ans f e r& s t ar t t r ans f e rs e que nc e ,t hepol ype pt i de ’ sNTe r mi nusr e s i de si nt he RERl ume nwhi l eCTe r mi nusr e s i de si nt hec yt opl as m. I tmakespr o t ei nwi t hmul t i pl et r ans membr anedomai ns . St ages Synt hes i soft hepol ypept i debe gi nsaf t eramRNA bi ndst oaf r eer i bos o me .Ast hefir s t s t ar tt r ans f e rs e que nc eemer gesf r om t her i bos omei ti sr ec o gni z edbyas i gnalr e c o gni t i on par t i c l e( SRP) ,t he SRP bi nds t o bo t ht he s t ar t t r ans f er s equenc e on t he nas c ent pol ypept i de & t he r i bos ome ,t empor ar i l y ar r es t i ng f ur t hert r ans l at i on bi ndi ng t o r i bos omeal s oi nc r eas esi t saffini t yf orGTPwhi l ebi ndi ngofSRPt os i gnals equenc ei nhi bi t s SRP’ sabi l i t yt ohydr ol yz et heboundGTP. TheboundSRPs er vesasat ag& enabl est heent i r eSRPr i bos ome nas c e ntc hai nc ompl e xt o bi nds pec i fic al l yt ot hec yt os ol i cs ur f ac eoft heERmembr ane . Thebi ndi ngt ot heERoc c ur st hr ought wos equent i ali nt er ac t i ons :oneb/ wt heSRPandt he SRPRe c e pt or ;andt heo t herb/ wt her i bos ome& t heTr ans l o c on. Onc et he SRPr i bos ome nas c e ntc hai nc ompl e xbi ndst ot heER membr ane ,t heSRP i s r e l eas edf r om i t sER r ec ept or ,t her i bos omebec omesat t ac hedt ot hec yt os ol i cendo ft he Tr ans l oc on ol y s i so fGTP bound t oSRP & SRP Re c e pt ort oGDP t r i gge r st he r e l e as eo ft hes i gnals e que nc ebyt heSRP& i t si ns e r t i oni nt ot heTr ans l oc on nGDPbound s t at e ,SRPhasl o w affini t yf orSRPRe c e pt o r . Thent hes t ar t t r ans f e rs e que nc eoft henas c entpol ypept i dei st heni ns er t edi nt ot henar r o w aqueousc hanne loft het r ans l oc on,di s pl ac i ngt hepl ug( Bi P)f r om t hec hanne l& openi ng t he pas s age way and t her e by al l o wi ng t he r emai ndero ft he pol ypept i de t ot r ans l oc at e t hr ough t hehydr ophobi cpor er i ngc o t r ans l at i onal l yi nt ot heRER l umen;e xc eptt heNTer mi nusi si nt hec yt os ol .Pos i t i ve l yc har gedami noac i dskeept heNTer mi nusawayf r o m t het r ans l o c on. Asas e c onds t r e t c ho fhe l i c alami noac i dst hatf unc t i onsasas t opt r ans f e rs e que nc eent e r s t het r ans l o c oni thal t st het r ans l oc at i onoft hepol ypept i det hr ought heERmembr ane .
Lecture 11 Endomembrane System
Course: Cell Biology (ZOOLOGY 570)
University: University of Wisconsin-Madison
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