The structure and function of serpins
The structure and function of serpins
The structure and function of serpins
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discovered this daes appearto happen: Z sntwrin rerdiiy<br />
pobmerized imo bng fibnh. whale hepatmfie indw~ns were<br />
found to conrirl <strong>of</strong> emangkd anutvpYin fibnb<br />
<strong>The</strong> model could also explain the rapidly pmgreirive liver cirrhe~<br />
(n 8nfancy. <strong>The</strong> foimation <strong>of</strong> pipmen ir highlyramperalure<br />
mstne. <strong>and</strong> wen comparatively mall incream in the<br />
range 37-41.C lead to vastly arreleraied rater <strong>of</strong> palymetira.<br />
fion. Such temperature ChMgel an occur in childhood feuen<br />
Indeed. m I pre~"ous tliniral nu* <strong>of</strong>U infant$ two children<br />
suddenly developed severe Iwr direaie ahv an unrelated fever.<br />
Confimiatm that fever was a piiiemially rigmfirant ttiggenng<br />
factor came fmm an unexpected IOYX~. DiJean-Yvvonne Bog<br />
fmm Rouen in Fmce had rem the Cambo$e gmup blood<br />
$amplel from pai,emi wnh familial thmmbdic direaie. In one<br />
family. indmduais ruiiered ~ccasional episodes <strong>of</strong> severe<br />
thromboiis aimciaed with plarma levels <strong>of</strong> amnhmmbin that<br />
were sometimes IOW <strong>and</strong> mnetimei nmal. <strong>The</strong> abnomi<br />
amiihmmbn turned out 10 comain an amino acid iubrtnuGon<br />
wh-th created a coniomtional instability - a ~ uieln~ with<br />
an oveneniilne tngger. In the t a tube. the abnoml<br />
amlhmmim slowly Convened tothe inaLtive ïnpgereS fon<br />
at 37'C but changed rapidly I 39'C polymenting in much the<br />
sme way ai Z anutpmim<br />
At fint these invertigattonr 01 mdividual mutations seemed to<br />
pmvide an imereniog but anecdotal study <strong>of</strong> genetc disea$e<br />
<strong>and</strong> moleiular m-hanirmr. Gradually. however. a pattern<br />
was began lo emege. MI only fmm the dwene moleLulai<br />
abnomaLUîS <strong>of</strong>imnhmmbin identified m Cambndge <strong>and</strong><br />
elsewhere k m patiemr wnhthmmbotic dileale. but ab0 fmm<br />
nudm dCImhbnwmcMt8om (n familsa1 angioedem. But<br />
the patem was fninratinghl inmmplate: forexampk. mmc<br />
rare al-amspmiin vaMnts had the rame ilinkal effects a$ the<br />
Z vanant. <strong>and</strong> all0 omed a caniormatimal innabilny reruHing<br />
in pelpme~tion. bin the molecular lnionr affeded qune di6<br />
rent mgions <strong>of</strong>the motccuic<br />
A SHARED PATHOLOGY<br />
ihe explanation for this shared molemlar pathology recently<br />
became apparent when &II the known piaims repin mutations<br />
were plotted an the 1hree.dimenrionaI lemplate nmum<br />
Over haK <strong>of</strong>the 100 mutationr dunered ~n fou? well-defined<br />
domains <strong>The</strong> interpretation <strong>of</strong>thii clme& WI greatly aisiil.<br />
ed bythe completion <strong>of</strong>the rryslul slmcture <strong>of</strong>two funher<br />
lam3 <strong>of</strong>snthhmmbin. eq~ivdlem 10 the paniy sprung <strong>and</strong> fuiw<br />
lrggered mouretrap. <strong>The</strong> tmnmon between these WO fomr<br />
rerub fmm P ttiggetinpindured change <strong>of</strong> iecondary wcture.<br />
uling this reiw af~onbmationt. Anhw Lerk <strong>and</strong> graduate<br />
nudent Jamer Mi$himotL produced I video showing how the<br />
mobile region mwei dvnng mppiog. <strong>and</strong> how spontaneous<br />
ttipgeting leads to polymercation. Amwding to thil Unetic<br />
model. three <strong>of</strong>the mutaionil domains invobe regions ileidy<br />
impliated in the trapping movements - the peptide loop con-<br />
taining the ban region. <strong>and</strong> its pmximal <strong>and</strong> diml hinges <strong>The</strong><br />
founh me was qune unexpected <strong>and</strong> has identified the m ob<br />
~bil~tch'<br />
that cornroll the entry dthe bait reepioo into the<br />
min body <strong>of</strong>the molecule.<br />
Mut11i~1 h any <strong>of</strong>thare domains lead to rpomaneour <strong>and</strong><br />
imppmpriate miornationai changer resulting, in the inhibitory<br />
iepnr. in a shared pathology <strong>of</strong> inaaivation. pol)m&ation<br />
<strong>and</strong> piarma deficiency. In paniwlar. the mutations in the 'Iatdi<br />
Cod this tsmperature ~ensil~ny explain the unu~uaily severe<br />
episodes <strong>of</strong>thmmborir in the Rwen family! Th6 queRion domain that occur in the rare deficiency ~ tiimi af antnryprin<br />
bm& an imediate faxed respame fmm France <strong>and</strong> pmvid. have the lame clinid dieai [ïier <strong>and</strong> lung areare) .a$ the<br />
ed one <strong>of</strong> thore erquirncly warding mmem that .xur<br />
only o~aiionalbf in a Lfetime <strong>of</strong> mearch. "Remakable ..,<br />
exinodinary"- he <strong>of</strong>the Y>: episodes <strong>of</strong>thmmborii in the<br />
family occumd dunng petio& <strong>of</strong> fee< one in a 20 year old<br />
mth pneumonia <strong>and</strong> four in family memben akei other fever-<br />
,ndvting<br />
mutation H the pmximal hinge in the 2 antnryprh vatianr<br />
<strong>The</strong> ,demification <strong>of</strong>thne mobile domaini has ~t only pmvided<br />
a satisfying explanation afthe common mdecdarpathology<br />
in the repin family but has also revealed the mechanisms (on.<br />
tmiling cdonnaiond changes in these proteins. ~n parnutar,<br />
dscare reruns from abmmal&rthat cause an inappropriate<br />
or pmmture change in ~~nformatloh Thur the wlnerabiïny <strong>of</strong><br />
these mobile mechanisms in the $vins pdder a pmlotype<br />
forthe much bmader group <strong>of</strong>diiodes now being recognized<br />
as ionfomational direaies.<br />
<strong>The</strong> Gas <strong>of</strong> L@:<br />
<strong>The</strong> physiological <strong>and</strong><br />
molecular effects <strong>of</strong> oxygen<br />
...<br />
7
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