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Transthyretin

Abstract
Transthyretinisaserumprotein,chieflysynthesizedintheliver,whosefunctionisof
vitalimportancetometabolism,cellulardifferentiation,anddevelopment.Transthyretin
primarilyservesasatransportproteinforthethyroidhormonethyroxine,themost
abundantofallofthethyroidhormonesproducedinthebody.However,transthyretin
canalsoformacomplexwithretinolbindingproteintoassistinthetransportofretinol.
Thyroxineisaprohormone,meaningthat,althoughitisactivetosomeextent,itisa
precursortoamoreactivehormonecalledtriiodothyronine.Bothhormonesareactive
intheirfreeforms,whichispreciselywhytransthyretinissoimportant.Lessthan1%of
allofthethyroxinesecretedintothebloodstreamisfree,whiletherestisboundbyone
ofthreetransportproteins:transthyretin,thyroxinebindingglobulin,orserumalbumin.
Thistightregulationofthethyroidhormoneskeepsmetabolismandcellular
developmentfunctioningproperly.
Structurally,transthyretinissimple,yetbeautiful.Itisahomotetramerthatismadeup
offourmonomersthatare127residueseach.Eachmonomerconsistsprimarilyof
sheets,buteachonealsocontainsasinglehelix.Hydrophobicinteractionsbetween
thesheetslendonemonomertoformastructuralmotifwithanothermonomer

1ContactJasonMockviaemail:mockj@rx.uga.edu

ortraditionalmail:DepartmentofPharmaceuticalandBiomedicalSciences
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knownasabetasandwich.Twoofthesedimerscanthenassociateinopposing
orientationstoformthetetramericcomplex,whichhastwoactivebindingsites
betweenthetwohomodimers.
Whilenormalfunctioningofthisproteinhelpsthebodytooperateproperly,abnormal
activitycanhavedireconsequences.Transthyretinisoneoftwentyknownsoluble
proteinsthatcanforminsolublefibrilscalledamyloids,whichcanthendepositinan
organ,causingdysfunctionandaconditionknownasamyloidosis.
Transthyretinamyloidosiscanresultfromthenormalsequenceoftheproteinorasa
resultofamutationthatcausesavariantformoftheprotein.Wildtypetransthyretin
amyloidosishasalateonsetandgenerallyaffectstheheart,althoughsomeother
organsmaybeinvolved.Whiletheexactstimulithatresultinfibrilformationarenot
known,thereisaclearcorrelationwithonsetandaging.
Therearemanydifferentvariantsequenceformsoftransthyretinamyloidosis.Nearly
80variantformsoftheprotein,resultingfrompointmutationsinthegene,havebeen
associatedwithsomeformofamyloidosis.Variantsequencetransthyretinamyloidosis
canaffectorgansotherthantheheart,liketheGItractorthecarpalligaments,butthe
heartandthenervesarecommonlyinvolved.
Lastly,inspiteofitsseeminglysimplestructure,transthyretinisactuallyvery
unique.Notonlydoitstwobindingsitesexhibitnegativecooperativity,arare
occurrenceasfarasproteinsgo,theyarealsoextremelyversatileintermsofthe
typesofligandstheycanbindasidefromthyroxine.Furthermore,theprotein
complexformedbytransthyretinandretinolbindingproteinisanimmense
structure,withmanynoteworthyaspects.

BackgroundandHistory
Transthyretinisaserumtransportproteinthatplaysaroleinthetransportof
thyroxine,athyroidprohormone,andretinol,viaacomplexwithretinolbinding
protein[1].Thoughtheprimarypurposeofthispaperistoaddressthestructural
intricaciesofthisprotein,aproperunderstandingofthehistory,function,and
clinicalrelevanceoftransthyretinisvitalinordertoappreciatethesignificanceits
structure.

Theevolutionofaname
Thecurrentunderstandingoftheproperties,structure,andfunctionof
transthyretin,shownbelowinFigure1,istheproductofmorethanfiftyyearsof
research.Initiallycalledprealbuminwhenitwasdiscoveredbecauseitseparated

aheadofalbuminonserumproteinelectrophoresisgels,thenametransthyretinwas
settleduponasinsightintoitsrolesinthebodywereelucidated.

AfterDewittGoodmanandcolleagues,whowereresearchingtheinteraction
betweentransthyretinandretinolbindingprotein,sequencedtransthyretinin1974,
theyattemptedtohavethenameoftheproteinchangedfromprealbuminto
transretin[2].However,othersbelievedthatitsroleinthetransportofthyroxine
wasmoreimportant,andtherefore,shouldprovideabasisforthename.Thus,in
ordertoappeasebothfactions,thenomenclaturecommitteeoftheInternational
UnionofBiochemistryandMolecularBiologyeventuallydecidedonthename
transthyretinin1981[1].

Bodilydistribution
Whilemosttransthyretinisproducedintheliveritisalsosynthesizedinseveral
othertissuesincludingthekidney[3]andthechoroidplexus[4].Ofcourse,
transthyretincanbefoundcirculatinginserum,whereitwasfirstisolated,but
subsequentstudieshavealsofounditpresentintheretinalpigmentepithelium,the
pinealgland,andpancreaticisletcells[5,6].Butperhapsmoreimportantly,
transthyretinmakesupasmuchas25%oftheproteincontentfoundinthe
cerebrospinalfluid[4].Withoutthehelpoftransport,transthyretinwouldhave
difficultycrossingthebloodcerebrospinalfluidbarrier;thus,theproductionofthis

proteinbythechoroidplexus,whichmainlyfunctionsintheproductionofthe
cerebrospinalfluid,isextremelyimportant.Experimentationhasvalidatedthis
theory,byshowingthatmostofthetransthyretinsynthesizedinthechoroidplexus
issecreteddirectlyintothecerebrospinalfluidratherthantheblood,establishing
thechoroidplexusasthepredominatesourceofthisproteininthecentralnervous
system[7].

Functionoftransthyretin
Notsurprisingly,thedistributionoftransthyretininthebodyisassociatedwithits
function.Transthyretinhastwoprimaryduties:totransportthyroxine,themost
abundanthormoneproducedinthethyroid,andtohelptransportretinolby
complexingwithretinolbindingprotein[1].
Transthyretinisoneofthreethyroxinetransportproteinsintheserum,theothers
beingalbuminandthyroxinebingingglobulin.Intheserum,transthyretinis
responsibleforbindingandtransportinganywherefrom1520%ofthethyroxine
present,butintheCNS,itbindsandtransportsupto80%ofthyroxine,makingit
theprimarythyroidhormonetransportproteinfoundinthecerebrospinalfluid[8].
Thebindingofthyroxineiscrucialtomaintainingappropriatelevelsofthis
hormoneintheplasmaandwithincells.Unboundthyroxineismetabolicallyactive,
andinitsactiveform,thyroxinecanhaveprofoundimpactsonacell,helpingto
facilitatecellulardifferentiation,development,andmetabolism.Thus,itis
importanttonotethattransthyretinandtheotherthyroidtransportproteinskeep
nearly99%ofthyroxineinitsbound,inactivestate.Thissurplusofthyroxineinthe
bodyallowsforsensitivesignaling,astransthyretincantransportthyroxineto
tissueswhereitisneededandquicklybindthehormonewhenitisnot[9].
Furtherexemplifyingthecorrelationbetweenlocationandfunction,transthyretinis
alsoresponsibleforassistinginthetransportofretinol.Asitwaspreviouslynoted,
mostserumtransthyretinissynthesizedintheliver,whichalsohappenstobethe
primarystoragesiteofretinol.Retinolistransportedtothemembraneoftarget
cellsbyassociatingwithretinolbindingprotein.However,retinolbindingproteinis
arelativelysmall,withamolecularweightof21,000Da,allowingittobereadily
filteredoutofthebloodbythekidneysandpreventingpropertransport[10].
Complexingwithtransthyretin,whichhasamolecularweightof~55kDa[11],
preventsglomerularfiltrationandincreasestheaffinityofretinolbindingprotein
forretinol,allowingtransporttotargetcellsmorespecifically[10].

BiologicalandGeneticAspectsofInterest
Whiletransthyretindoesnotfunctionenzymaticallyorundergoanyexciting
conformationalchanges,itsfunctionwithinthebodyiscrucial.Asthenextsection
willdescribe,transthyretinisinvolvedinthedevelopmentofseveraldiseases,and
thebiologicalandgeneticvariabilityoftransthyretinthathasbeenimplicatedinthe
formationofthesediseaseswillbecoveredindetail.


Diseasestatesrelatedtotransthyretin
Amyloidosisisadiseasestatecharacterizedbydepositsofinsolubleproteinfibrils
thatcanaccumulateinvarioustissuesthroughoutthebodyandinterferewiththe
normalfunction[1].Therearearoundtwentyproteinsandpolypeptides,ofwhich
transthyretinisone,thatareknowntobeassociatedwiththistypeoffibril
formation,andwhiletheexactmechanismoffibrilformationremainsamystery,all
fibrils,regardlessoftheirparentprotein,sharethreetraits:fibrilsstronglybindto
thedyeCongored,theyarelong,unbranched,andgenerallyhaveadiameterof
approximately100,andtheyconsistofsheetsthatcrossparalleltotheaxisof
thefibril[12].
Ofthevariousamyloiddiseases,includingprionandAlzheimersdisease,
transthyretinisspecificallylinkedtofamilialamyloidpolyneuropathy,familial
amyloidcardiomyopathy,andsenilesystematicamyloidosis.Infamilialamyloid
polyneuropathy,mostamyloiddepositsformintheheartandperipheralnerves
[13],andalthoughthisdiseaseisusuallyaresultoftransthyretinfibril
accumulation,geneticvariantsofapolipoproteinA1havealsobeenknowntoresult
inthiscondition[1].Bothfamilialamyloidcardiomyopathyandsenilesystematic
amyloidosisusuallycauseamyloidbuildupintheheart,andmaybeoneofthe
causesofunexplainedcardiomyopathyandarrhythmia[14]
Thediscoveryoftransthyretinsroleinamyloiddiseasewasmadein1978when
Costaetal.showedthatamyloidmaterialtakenfromcertainpatientsreactedwith
antiserumofplasmatransthyretin[15].Thisfindingacceleratedresearch
associatedwithtransthyretinandhowamyloiddiseasesdevelopfromendogenous
proteins.
Recentresearchhasexpandedourunderstandingofhowthesefibrilsform.Inthe
caseoftransthyretin,thehomotetramermustdissociateintomonomers,whichcan
thenassembleintoamyloidfibrils[14].Itislikelythatthesefibrilsassemble
heirchially,withindividualpolypeptidesformingprotofilaments,whicharethought
tobecomposedofsheetsthattwistaroundoneanotheroracore,whichmayor
maynotbehollow.Jaroniecetal.usedmagicanglespinningNMRtodeterminehow
anamyloidfibrilmightformfromapolypeptideregionoftransthyretin.Magic
anglespinningNMRisuniqueinthatitallowedtheresearcherstocircumventthe
problemofalackofroutinestructurethathadpreventedelucidationviaxray
crystallographyandnormal,liquidstateNMR.Theyshowedthatan11residue
fragmentoftransthyretin,whichisshowninFigure2,wascapableofself
assemblingintoanamyloidfibril[12].Theseresultsprovidevaluableinsightinto
howthisdiseasemayprogress.

Naturallyoccurringvariantsoftransthyretinandamyloidosis
Whilemostamyloiddiseasesareconsideredtobeproductsofregularaging,in
whichthewildtypeproteinbeginstoformfibrilsthatwillthenaccumulateasan
individualgetsolder,thereareapproximately80knownpointmutationsof
transthyretinthatareassociatedwithinheritedamyloidosis[1].
Ofthesevariants,roughly70areknowntocontributetothedevelopmentoffamilial
amyloidpolyneuropathy,whileonlyafewareassociatedwithfamilialamyloid
cardiomyopathyandsenilesystematicamyloidosis[14].Thediscoverythat
variantsoftransthyretinarecloselyrelatedtoamyloidosisinitiatednewdirections
inresearch,bothmolecularlyandgenetically.Someresearchersbeganlookingat
thyroxinebindinganditsinvolvementindiseaseprogression,whileothershunted
forthesequenceofthegenebehindtheproblematicprotein.
Ingeneral,thesevariantmutationsareautosomaldominant,meaningthatan
individualcanhaveonewildtypeandonemutantalleleandstillexhibita
phenotype.Mostcarriersareheterozygous,andinterestingly,theyusuallyexhibit
mostlynormalproteinintheplasma,eventhoughitisassumedthatbothallelesare
transcribedequally[16].Attemptsweremadetodefine3Dstructuresofthese
variantsinordertoextrapolatewhytheymaybemorepredisposedtoforming
amyloidfibrils;however,thisundertakingwascomplicatedbythefactthatmost
individualswithamutationareheterozygous,andtransthyretinhasauniqueability

toformhybridtetramers,inwhichanyofthemonomersubunitscanbeavariant
orwildtypeformoftheprotein[1].Thisinterestingaspectoftheproteinmadethe
elucidationofitsgenesequencethatmuchmorecrucial,asrecombinantDNA
technologiescouldprovideamorefeasibleapproachtostudyingtheoveralleffects
ofthesemutationsontheproteinstructure.

Sequencingofthetransthyretingeneanditsuseinresearch
AlthoughothergroupshadreportedthesequenceofthecDNAofhuman
transthyretin[1],thecompletegenesequencewasnotelucidateduntil1985by
Tsuzukietal.Therearethreeintronsseparatingthefourexonsofits6,945bp
sequence,andoddly,therearetwoopenreadingframeswithinthefirstandthird
introns(oneineach,respectively),butitisnotknownwhetherornottheseORFs2
areactuallyexpressed[17].Thegeneislocatedonthelongarmofchromosome18
[18],anditsaccessionnumberisNC_000018.
Ofcourse,aftersequencingthehumantransthyretingene,theputativenextstepin
determiningtheprocessoffibrillogenesisandamyloidosiswastocreatea
recombinantanimalmodel.Thegenewasalsosequencedinmice,anditwas
extremelysimilartothehumangene:containingthesameconservedsequences,
hepatocytespecificbindingsites,andchangesinonly25outofthe127residues.
Yet,fibrilscontainingtransthyretinhaveneverbeenobservedinmurine
amyloidosis[19].Researchershopedtoovercomethisbygeneratingrecombinant
micethatwouldexpressvariantformsofhumantransthyretin,andwhilemany
havetried,therehavebeenvaryingamountsofsuccess.Althoughresearcherswere
abletocauseamyloidformationsintheirmousemodels,therewasneverany
accumulationintheperipheralnervoustissue,whichisoneofthehallmarksof
transthyretinrelatedamyloidosis.So,althoughthereasonwhyaccumulationnever
occurredintheperipheralnervoustissueisnotcompletelyunderstood,itisclear
thatamousemodelwillnotsufficeasamodelsystemforstudyinghuman
transthyretinamyloidosis[1].

StructuralBiology
Asmentionedabove,transthyretinisanextremelyimportantproteinintermsof
regularbodilyfunctionanddiseasestates.Althoughtransthyretiniscomposedof
fouridenticalmonomers,unlessanindividualisexpressingoneofthe
aforementionedvariantformsoftheprotein,itsstructuralfunctionsare
surprisinglydiverse.Inthenextsections,thestructuralbiologyoftransthyretinand
howitbindsthyroxine,exogenoussubstrates,andretinolbindingproteinwillbe
covered.

2ORF=OpenReadingFrame

Structure
Aspreviouslystated,transthyretinisahomotetramer;however,itsstructureis
anythingbutlackluster.Transthyretinmonomersarecomposedprimarilyof
sheetsinasandwichorientations,withoneshorthelix,consistingofonlynine
residues.Around45%oftheremainingaminoacidsmakeupthemonomerseight
strands.Asaresultofsevenaromaticresiduesonthesideoftheproteinopposite
thehelix,thesheetsaremorespreadoutatthatend,asopposedtothesections
ofthesheetsthatareclosertothehelix,whicharetightlypacked[1].
Themonomersformdimersviaextensivehydrogenbondingatapseudotwofold
axisofsymmetry.Thehydrogenbondsoccuralongtwopairsofstrandsinwhich
theresiduesarecloselyjuxtaposed[1].Thesestandsandtheiradjacentresidues
canbeseeninFigure3,coloredmagenta.Thisbroadareaofhydrogenbonding
allowstransthyretintoreadilyformdimersthatareextremelystable,which
accountsforthefactthatthedimeristhebasicunitofthisproteininvivo,rather
thanthemonomer[9].


Unlikethetightlyassociateddimers,thetetramericformoftransthyretinisnot
quiteasstrong.Thereisonlyasmallcontactregionbetweentheloopsofonedimer
withthesheetsoftheother.Thisbondresultsprimarilyfromhydrophilicand
hydrophobicinteractions.Theseimportantloopregionscanbeseenhighlighted
aboveinFigure4.Impressively,inspiteofthesmallareaofcontact,transthyretin
tetramershavebeenshowntobestableinapHrangebetween3.5and12[1].
However,themostimportantaspectoftheformationofthistetramericstructure
arethebindingsitesthatitcreatesforthyroxine.

ThyroxineBinding
Thyroxineisthenaturalligandfortransthyretin.Therearetwobindingsitesfor
thishormone,bothofwhicharelocatedinthechannelthatisformedbythe
tetramericcomplex.Eachsiteisapproximately50longand8wide,andis
capableofbindingonethyroxinemoleculeatatime[1].
Ataglance,theaboveinformationwouldmaketransthyretinseemcommonplace,as
farasproteinsgo;however,itisactuallyexceptionallyuniqueinseveralways.
First,althoughtherearetwobindingsitespertetramer,transthyretinexhibits
negativecooperativity,meaningitwillonlybindonemoleculeofthyroxineatatime,
andtheotherbindingsitewillremainvacant.Negativecooperativityisrare

amongstproteins,andinthecaseoftransthyretin,itoccursbecausethediameters
ofthetwobindingsitesareslightlydifferent[20].
Thebindingsiteisdividedintothreepartscalledhalogenbindingpockets3,orHBPs
[14].TheprimarybindingsiteiswiderattheouterandinnerHBPsandmore
restrictiveinthemiddlepocket,whiletheoppositeistrueofthesecondarysite.
Thus,thyroxinecanmoreeasilyenterandbindintheprimarysite.Oncebound,
thyroxinecausesanincreaseinthediameteroftheprimarysite.Thisslightchange
instructureresultsinachangeinconformationatthesecondarysite.Despitethe
factthatthesesitesarenotdirectlyconnected,thechangeinonesitecanbefeltin
theotherduetothestronghydrogenbondsconnectingthemonomers[20].
Theconformationalchangeinthesecondarysiteresultsintheopeningofthesiteso
thatthedimensionsaresimilartothatoftheinitialprimarysite.Thus,athyroxine
moleculemayenterthesecondarysite,butifthisoccurs,itwillforcea
conformationalshiftintheoppositedirectionastheonethattookplaceafterthe
firstligandwasbound.Sincethefirstthyroxinehasalreadyestablishedbinding
interactionswiththeprimarysite,thisbackwardsshiftcannotoccurasreadily,and
theconformationalchangesthatwouldbenecessarytotightlybindthethyroxinein
thesecondarysitecannottakeplace.Asaresult,thesecondarysitewillnotbind
thyroxineafteramoleculeofthehormoneisboundintheprimarysite,thus
explainingthenegativelycooperativenatureoftheprotein[20].
Furthermore,transthyretinisuniqueinitsmodeofbindingthyroxine.Thebinding
sitesforthyroxinearelocatedwithinatwofoldaxisofsymmetrybetweenthetwo
dimersofthetetramericcomplex.Asaresult,thebindingpocketitselfhasatwofold
axisofsymmetry,whichallowsthethyroxinemoleculetobindintwodifferent
modesororientations.AsshowninFigure5,athyroxinemoleculecanfaceeither
waywithinthebindingsiteandstillhavethenecessaryinteractionstoremain
bound.Ineithermode,thehydrophilictailofthyroxineispositionedattheopening
ofthebindingsitetoexposeittotheaqueousenvironmentandthesameactive
residues,detailedinFigure5,interactwiththerestofmolecule,withthe
conformationalchangesdescribedabovemakinghydrogenbondingpossiblewith
eitheralignmentofthemolecule[14].
TheseactiveresiduesarearrangedintothreeunitscalledHalogenBindingPockets,
orHBPs,and,asthenamesuggests,theyinteractwiththeiodineatomson
thyroxine.HBP3istheinnermostpocket,coloredblueinFigure5,anditconsists
ofSer117,Thr118and119,Ala108and109,andLeu110.HBP2,coloredcyanin
Figure5,sharesLeu110andAla109withHBP3,butalsocontainsLys15,andLeu
17.Lastly,HBP1,theoutermostpocket,ismadeupofAla108,Thr106,Met13,and
Lys15,anditiscoloredmagentainFigure5[14].

3HBP=HalogenBindingPocket


Therelativeversatilityofthebindingsitesoftransthyretinisnotonlysignificant
withrespecttoitsbindingofthyroxine,butalsotonaturalandexogenousanalogues
ofthehormonethatmaybeofclinicalimportance.

Theimportanceofothersubstrate
Todate,theonlyeffectivetreatmentforfamilialamyloidpolyneuropathyisliver
transplantation[Original],asmosttransthyretinisproducedwithintheliver,but
sincestudieshavesuggestedthatvariantproteinproductioninthechoroidplexusis
morelikelytobetheprimarycauseofthiscondition,itisanincompletesolutionat
best[21].
However,thereisstillhopeinthefighttoslowtheprogressionofthisdiseaseand
theothertransthyretinassociatedamyloiddiseasesintheformofthyroxine
analogues.Thesemoleculesactasinhibitorsoftransthyretinamyloidosisby
bindingintheactivesite,whichstabilizesthetetramericstructureoftheprotein.
Sincetransthyretinhastodissociateintomonomersinorderforfibrillogenesisto
occur,thestabilizationofthenativetetramericformoftheproteincouldprovidea
therapeuticapproachtoslowingtheprogressionofamyloidosiswithouttheneed
forinvasivesurgery.Figure6showsthestructureofthyroxine,flufenamicacid,
resveratrol,andoFLU,fourmoleculesthatbindtransthyretinandare
representativeofdifferentclassesofamyloidosisinhibitors:thenaturalligand,non
steroidalantiinflammatorydrugs,naturalcompounds,anddesignedamyloidosis

inhibitors,respectively[14].Thankstoitsflexiblebindingsites,therearemany
otherexamplesofmoleculesthatcanbindtransthyretinaswell,butthoseshownin
Figure6shouldprovidesomeideaofthetypesofclassesandgeneralstructuresof
thesepotentialamyloidosisinhibitors.

RetinolBindingProteinComplex
Asidefromtransportingthyroxine,transthyretinisalsophysiologicallyimportant
foritsroleintransportingretinol,orvitaminA.Retinolisstoredintheliver,andin
ordertobesecretedtoothertissuesitmustbindretinolbindingprotein4,orRBP,in
ahandinglovemanner,inwhichtheretinolmoleculefitssnuglyintotheeight
strandbarrelthatmakesupthemajorityoftheRBPstructure[11].However,a
singlemoleculeofRBPisonly21kDa,anditcanreadilybefilteredoutoftheblood
streambytheglomerulusinthekidneys,preventingRBPfromdeliveringretinolto
thetissuesthatneedit.Luckily,thisproblemcanbeovercomewhenRBPformsa
complexwithtransthyretin[1]
Thistransportcomplexconsistsofonetetramerictransthyretinmoleculeandtwo
RBPs.EachRBPbindstransthyretinataninterfacebetweentwomonomersina
twofoldaxisofsymmetryonoppositedimers.Eachtransthyretinmonomer

4RBP=RetinolBindingProtein

contributesfouraminoacidresiduestothebindingsite:Arg21,Val20,Leu82,and
Ile84.Theseeightresiduesfromtransthyretinprovideaninterfaceforinteraction
withfourresiduesfromRBP:Trp67,Phe96,andLeu97and63.Furthermore,
extensivehydrophobicinteractionbetweentheCterminusofRBP,whichhasan
helicalsecondarystructure,andtransthyretinensurethattheproteinsstaytightly
boundwhileincirculation[11].Thesecontactpointsarehighlightedbelowin
Figure7.

ThetransthyretinRBPcomplexisextremelyimportantforretinoltransportnot
onlybecauseitwouldscarcelytakeplacewhereitnotforcomplexion,butalso
becausethebindingofRBPtotransthyretinincreasestheproteinsaffinityfor
retinol,whichhelpspreventnonspecificdeliveryofretinoltounintendedtarget
tissues[10].
Additionally,itmaybeofinteresttonotethatpointmutationscausinggenetic
variantsoftransthyretincanhaveaprofoundimpactonretinoltransportand
distribution.Asingleaminoacidsubstitutionatposition84canproducedramatic
effects,emphasizingthisresiduesimportancetothebindingprocess.Specifically,
individualsthathaveapointmutationthatsubstitutesthewildtypeisoleucineat
thispositionwithserineorasparaginehadsignificantlydecreasedamountsofRBP
incirculation,asitwasunabletoformthetransportcomplexwithtransthyretin
[22].

Conclusion
Insummary,transthyretinisanextremelyuniqueserumtransportprotein.It
facilitatesthetransportofthethyroidhormonethyroxineandretinolviaaversatile,
negativelycooperativebindingsitesandamultiproteintransportcomplex.
Furthermore,asidefromitsnormalrolesinthebody,itcanalsoplayarolein
diseaseformationthroughaprocessknownasfibrillogenensisthatresultsin
amyloidformationsinvarioustissues.Thus,athoroughunderstandingofthis
proteinanditsstructureisnotonlyrelevantinaphysiologicalsense,butalsoin
termsofclinicalapplication.

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