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Wtd021996.Pdf The Case of the MolectlEar Mowetnap: The structure and function of serpins 3 The rerpinr are highly eifenive pmteaie inhibitm. tenaciously gnpping their pmtcin target So ruccerrful is thc leipin mecha- nism that an emodinanly diverie range of adaptations has evolved. In some rerpinr inhibitoiy act~ilyis anwaled by par- timlii ligands. In some ofthe rerpini' more disant mlatber. inhtbtoiy artivly has been lost altogether and eherfunnronr gained. II in the homone ciden thymxine- and cortiro. stemid.binding globulini. Serpinr aie partiwlady important in the conml ofpmteoiflic carcadeder in the blood ansthmmbin inhibits blood clotting. CI-inhibitor c~nmlsmmplement anbation. and the inappm- pnately named SI-antitiypGn inhibits the elartare releasedby inflammatoiy leukocltei. Abnomalitiei of plarma rerpini are iurptisingiy common. and cause a vatiefy of direares - mainly of the dmilation.Ai many as one in a loo0 people har an amnhmm. bin abnomab, and ths a predspmiuon 10 thmmbosiit. The best-studiedabnormal sepini are ~mamofol-anti. Wdn. Some IO per cent of Eumpeam <anyone oftwo mylationi (5 or 7.) that mwlt in a mild (S) or severe (2) plaima deficiency ofthe Inhibitor. About I ~n2wO Eumpeanr caqE combination alvanant genes (ZZ or Si),reeruhing ins severe al-antilvprin deficiencF inhib&totorleveliare imulciem to pmten the elarric tissue ofthe lungs. leading to the dennrc- Dve disease emphysema in adulthood. Although Z antnn>rin is wtheiized in homqgoter. it is ineiütiently secreted. Innead. 4 discovered this daes appearto happen: Z sntwrin rerdiiy A SHARED PATHOLOGY pobmerized imo bng fibnh. whale hepatmfie indw~nswere The of ihe explanation for this shared molemlar pathology recently Gas L@: found to conrirl of emangkdanutvpYin fibnb became apparent when &IIthe known piaims repin mutations The physiological and The modelcould also explain the rapidly pmgreirive liver cir- were plotted an the 1hree.dimenrionaIlemplate nmum rhe~(n8nfancy. The foimation of pipmen ir highlyrampera- Over haK ofthe 100 mutationr dunered ~nfou? well-defined molecular effects of oxygen lure mstne. and wen comparatively mall incream in the domains The interpretationofthii clme& WI greatly aisiil. range 37-41.C lead to vastly arreleraied rater of palymetira. ed bythe completion ofthe rryslul slmcture oftwo funher fion. Such temperature ChMgel anoccur in childhood feuen lam3 ofsnthhmmbin. eq~ivdlem10 the paniy sprung and fuiw Indeed. m I pre~"oustliniral nu* ofUinfant$ two children lrggered mouretrap. The tmnmon between these WOfomr suddenly developed severe Iwr direaie ahv an unrelated fever. rerub fmm P ttiggetinpinduredchange of iecondary wcture. Confimiatm that fever was a piiiemially rigmfirant ttiggenng ulingthis reiw af~onbmationt.Anhw Lerk and graduate factor came fmm an unexpected IOYX~. DiJean-YvvonneBog nudent JamerMi$himotL produced Ivideo showing how the fmm Rouen in Fmce had rem the Cambo$e gmup blood mobile region mwei dvnng mppiog. and how spontaneous $amplel from pai,emi wnh familial thmmbdic direaie. In one ttipgeting leads to polymercation.Amwding to thil Unetic family. indmduaisruiiered ~ccasionalepisodes of severe model. three ofthe mutaionil domains invobe regions ileidy thromboiis aimciaed with plarma levels of amnhmmbin that impliated in the trapping movements - the peptide loop con- were sometimes IOWand mnetimei nmal. The abnomi taining the ban region. and its pmximal and diml hinges The amiihmmbn turned out 10 comain an amino acid iubrtnuGon founh me was qune unexpected and has identifiedthe mob wh-th created a coniomtional instability - a ~uieln~with ~bil~tch'that cornroll the entry dthe bait reepioo into the an oveneniilne tngger. In the tatube. the abnoml minbody ofthe molecule. amlhmmim slowly Convened tothe inaLtive ïnpgereS fon Mut11i~1h any ofthare domains lead to rpomaneour and at but changed rapidly I polymentingin much the 37'C 39'C imppmpriate miornationai changer resulting, in the inhibitory sme way ai Z anutpmim iepnr. in a shared pathology of inaaivation. pol)m&ation Codthis tsmperature ~ensil~nyexplain the unu~uailysevere and piarma deficiency. In paniwlar. the mutations in the 'Iatdi episodes ofthmmborir in the Rwen family! Th6 queRion domain that occur in the rare deficiency ~tiimiaf antnryprin bm& an imediate faxed respame fmm France and pmvid. have the lame clinid dieai [ïier and lung areare) .a$ the ed one of thore erquirncly warding mmemthat .xur mutation H the pmximal hinge in the 2 antnryprhvatianr only o~aiionalbfin a Lfetime of mearch. "Remakable ... .., The ,demification ofthne mobile domaini has ~t only pmvid- exinodinary"-he ofthe Y>: episodes ofthmmborii in the ed a satisfying explanation afthe common mdecdarpathology family occumd dunng petio& of fee< one in a 20 year old in the repin family but has also revealed the mechanisms (on. mth pneumonia and four in family memben akei other fever- tmiling cdonnaiond changes in these proteins. ~nparnutar, ,ndvting dscare reruns from abmmal&rthat cause an inappropriate At fintthese invertigattonr 01 mdividual mutations seemed to or pmmture change in ~~nformatlohThur the wlnerabiïny of pmvide an imereniog but anecdotal study of genetc disea$e these mobile mechanisms in the $vins pddera pmlotype and moleiular m-hanirmr. Gradually. however. a pattern forthe much bmader group ofdiiodes now being recognized was began lo emege. MI only fmm the dwene moleLulai as ionfomationaldireaies. abnomaLUîS ofimnhmmbin identified m Cambndge and elsewhere km patiemr wnhthmmbotic dileale. but ab0 fmm nudm dCImhbnwmcMt8om (n familsa1angioedem. But the patem was fninratinghlinmmplate: forexampk. mmc rare al-amspmiinvaMnts had the rame ilinkal effects a$ the Z vanant. and all0 omed a caniormatimal innabilny reruHing in pelpme~tion.bin the molecular lnionr affeded qune di6 rentmgions ofthe motccuic 7 OXYGEN OXYGEN The immediate response to hypoxia il an inreare in vermla. tim. the volume of air bmthed in and out per wit time. This appears to be a dires ellecl Of lowered blood oxygen level$, Ar ventilillion tirer. however. more arbon dioxide 1s exhaled. IO le~llin the blood fali: the cirdation becomes mmilCa. line. which. thmugh a reflex rerponre. causes venulatim ta fall .. -. towadi 1:s rUning poinL In a third phare. venUlaiDn increais RV- Orrm~'Imn h~o~(ml ID*cW that rmtml them. A bener underrtandingwould not jun have again overthe ncn iew days, and !hi$ inmase il %stained implirationt for athletes and dimben: it could also have clinical white the penon rrmaini at high al6tude -an cfl~tbown as ramificationsforthe miilions dpeopie with 811neiie1such II - - ~entill~~acdimtization. anhma and emphylema, which nowk in IOWlevels of oxygen in the body, or commry anery direare and cancer. where pmitu- Many hypotherer have been put ionvard to explain ventilatory lac tirruer are expored to hypoxid. acdimatimion to hypoxu. and mon have pmpored that aliui. Immtion ofthe blood and body times is a key phyriological Two grnupi funded by the Weltome Tnin are continuing tngger. This may seem paradoxicalsince. in the rhon.tem. ûxlodr Iraditionof hypoxia reIeaKh. by loollng at two dinincl rll<alinbstionlow~rr venulalion ratherthan increaiei it: haw- aspess of oxygen renrinp the phyriologml mechanism that ever. it is thought that, over longer timercalei. aliuiliniiition IEÜ Nu regulate breathing and the molecular merhantrmr unde+$ in train a 5eric1 of changer that ultimately have the OppoIite oWen.dependent gene exprerrion. ellecl. Nevenhelerr. although these hypotheiei have been immd for many yeas, there is 18nk dms evidence that alh- linizati~nunderlier ventilatory arciimatmtion. and Oc Robbinr A PHISlOLOGlCALAPPROACH wanted to investigate whether it is really nereüary. At the Vnwnny laboratory aï Phyliolqy in Oxford. Or Peter To do thil. he needed to devise a way of looking at the erect Robbinr and deaguei areulhgto undenlandhow pmlonged of IOW oxygen in isolationfmm fatir obon dioidc. The hypoxia afleni the breathing aihealthy humans. This queloin is in IOIYUO~was to enimate the amount of oxygen and cabon not 13 nraighüoFnard si n might seem. II the blood levels of dioxide in wbjed blood by mearuringtlte levels Ui exhaled b31h oxygen and carbo dioide change when the oxygen level$ ail: the composition ofthe airinhaled can then be adiuned m the asr fall. and both thele biton sflecl brealhlng. accordingly, to keep the carbon dioxide in exhaled air at nor- E 9 OXIGEN OXIGfN genes, which encode pmleinr that ran readily be deleRed The gmvp is alro adopting a genetic appmach and mmfing when transcription ii activated. Under nomal ciriumrtanrei. to irolafe mutam cells wnh dd&e sipmliing pathwas The eryhmpoietin is pmduced in the liver and Kdney. but hypoxia hypoxiahdurible wnlml elmahas been ïmMm 1 was found to induce repmw gene exprestian in 1 much repanw gene encdding IBu-xeiR markwpmltin'whm bmader range ofcell types - indeed every cell type tened IO this comporite gene is mfmedinm mammaïi (dis mml far has expressed the reponer gens in a hypmixically inducible cell$ 'light up' in niponle m hrpwia lia cell ir inras& U) faihtoh and all these cell typer also contain HIF- I. Thur. there hypmii 11ii likely to be &np a muration affectmgthe oy- appearr to be I similar mechanian for contmllinggene exprer. gen.redng pathway. The affectedgene ran tha be imlatcd sion in wpponre 10 hypoxia in most if not dl tirruer. cloned and analyred. what other genes might be ieniitive to hypoxial Dr Ratclifle This type ofgenelic analpis wriuld be much eaYa in anown. $taled with some educated gu~~rkhypoxia might be ian such
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