Cal

modul
i
n

Calmodul in,orcalcium- modulatedpr otein,isacal ci

um-
bindingpr ot ei
nf oundi nthecytoplasm ofal leukaryoti
c
cells.Itinteractswi thmanyot herpr oteinsi nthecell,
and
actsasar egulatororanef f
ectormol ecul einawi dev ari
ety
of cellularfunct i
ons.Thesef unct
ionsi ncludet hingsas
diverseasr egulationoft hecellcycle,intracell
ular
signal l
ing,ferti
li
zation,andmuscl econt racti
on.Cal moduli
n
i
s inaf ami lyofpr oteinsalongwi t
ht roponi nC, another
essent i
alcalci
um-bindi
ngprotei
ninvolvedi nmuscl econt ract
ion.Calmodul ini sanessent i
al
protein;mutati
onstoanyoft hecalmodul i
n-encodi nggenesordamaget othecal modulin
bindingsitesoftenprov
eslethal
.

Cal
modul
i
nSt
ruct
ure

Calmodulinisapr ot
einmadeupof148ami noacidr esidues.I tisencodedbymul t
ipl
egenes;in
humans: CALM1, CALM2, andCALM3whi charefoundonchr omosomes14, 2,and19,
respecti
vely.Calmodul i
nformst woglobul ardomainsconnect edbyaf lexibl
ecent rall
i
nker.
Eachdomai nbindst wocalcium i
onsi nE- Fhandmot ifs,amot ifubiquitousincal ci
um- bi
ndi
ng
protei
ns,sot hatcalmodulincanbindat otaloffourCa2+i ons.Thecal cium bindingsitesar
e12
aminoaci dslongandcont ai
nmanynegat i
vely
-chargedorpol arami noaci dresiduessuchas
aspartat
e, gl
utamat e,andasparagine.Thesi dechainsont heseami noaci dsf ormi oni
cbonds
withtheCa2+i ons.Otherami noacidresidueswi t
hsi dechai nsr ichinoxy genat omsal soatt
ract
thecalci
um cat ions.Thispromotesbindi ngevenatv erylowconcent rationsofCa2+.

Whencalcium i
sboundt ocalmoduli
naheli
x-l
oop-hel
ixisfor
medal ongthebackboneanda
confor
mationalchangeoccurs.Thi
sconfor
mat i
onalchange,coupl
edwi t
hthefl
exibi
l
ityoft
he
prot
einduetothef l
exi
bleconnecti
ngli
nker
,al
lowscalmodulintoint
eractwit
handbindt oa
widevari
etyofotherpr
oteins.

Thi
sfi
gur
edepi
ctst
hest
ruct
ureofcal
modul
i
nwi
thf
ourcal
cium i
onsbound.

Cal
modul
i
nFunct
ion

Cal
modulini
saubiqui
tousregul
atorpr
otei
nthati
sinvol
vedi
nmanycalcium-
mediat
ed
pr
ocesses.WhenCa2+bindstocalmoduli
nitf
ormstheCa2+/cal
modul
incompl
exwhicht
hen
i
nter
actswit
hotherprotei
nsinthecel
l
.Theseprotei
nsareenzymesandeffect
orprot
eins
i
nvol
vedinav ar
iet
yofcell
ularandphysi
ologi
cal
processes.TheCa2+/
cal
modulincomplexcan
al
soregul
ateprocessesdi
rectl
y.

Oneoft hefunct
ionsoftheCa2+/
calmoduli
ncomplexistoacti
vat
ecalci
um pumps.These
pumpsr emov ecal
cium f
rom t
hecyt
oplasm byei
therpumpi
ngitoutofthecellorst
ori
ngiti
n
theendoplasmicret
icul
um.Bycontr
oll
i
ngt heamountofcal
cium i
nthecell
,thedownstr
eam
responsesareregul
ated.

Furtherexampl esofCa2+/ cal

modul i
ncompl ex
funct i
onincl
udebi ndingt oCa2+/ calmodulinkinases
(CAMK)suchast hemy osinli
ghtchainkinase.This
bindingallowst heCAMKst ophosphoryl
ateeffector
proteinsbyt r
ansferringphosphat esfrom ATPt o
serineandt hreoniner esiduesont hereceivi
ng
proteins.Thesepr oteinst hengoont oact i
vate
downst ream processessuchasi ntr
acell
ular
signalli
ng,smoot hmuscl econtracti
ons,
neur otr
ansmitterandhor monesy nthesisandr el
ease,
andcel lcycl
er egulation.

Thisfi
gureshowsanexampleofhowcalmodul
in(
CaM)canbei
nvolv
edinacomplexpathway
i
napost -sy
napti
cneur
on.Thepathwayshownher
eist
heKEGGpathwayinhumandrug
addict
ion.

Cal
ci
um

Iti
sbecomingincreasi
nglyappar
entt hatcalci
um play
sacr ucialr
oleinanumberof
physiol
ogi
calpr
ocesses.Whennoti nuset heconcent
rati
ongr adi
entofcalcium ionsbetween
theinsi
deandoutsideofthecell
isv erylarge;
theconcentr
ati
onofext racel
lularcalci
um i
s
approxi
matel
y1mM whi l
etheconcent rati
onoffreecalci
um ionswithi
nt hecellislesst
han0.1
μM.Thisisli
kel
yduet othefactthatcalcium wil
li
nter
actreadilywi
thmanypr otei
ns.

Themaj or
it
yofcalcium inthecell
enter
sthroughgatedcal
cium channel
s.I
tcanalsobestored
i
nt heendoplasmi
cr et
iculum.Thecalci
um channel
sarelar
getrans-membraneprotei
nst
hat
al
lowpassageofi onsintothecellwhenaspecif
icsti
mulii
smet .thi
susual
lyoccur
swhent he
membr aneisdepolari
zedoral i
gandisatt
ached.