Medical Microbiology

298 4 BacteriaasHumanPathogens

tionofthetoxinandformationoftheso-calledtoxin-coregulatedpili(TCP)

onthesurfaceoftheVibriocells.

Pathogenesisandclinicalpicture.Infectionresultsfromoralingestionofthe

pathogen.Theinfectivedosemustbelarge(>– 108 ),sincemanyvibriosare

killedbythehydrochloricacidingastricjuice.Basedontheirpronounced

stabilityinalkalineenvironments,vibriosareabletocolonizethemucosa

MechanismofActionofCholeraToxin

Membrane

Outside 1 2

Cytosol

Receptor

Inactive

GS protein

Inactive

adenylate

cyclase Apctivrotee Ginsα

(Gsα-GTP)

Inactive

adenylate

cyclase

R

GDP

γ E

β

R

γ

β

GTP

E

Signal

3 4

Inactive

adenylate

cyclase

R

GTP

γ E

β

R

γ

β

GDP

E

Inactive

Gs protein

α

α α

α

Active complex

Gsα-GTP–adenylate cyclase

ATPcAMP

GSα-GTPase

Cholera toxin (CTA 1 )

inactivates the GTPase

activity of Gsα by means

of ADP-ribosylation

Fig.4. 20 CholeratoxindisruptstheGsprotein-mediatedsignalcascade.

1 TheGsproteinsinthemembranecomprisethethreesubunitsa,b,andc.GDP

isboundtosubunita.Gsisinactiveinthisconfiguration.

2 AfterasignalmoleculeisboundtothemembranereceptorR,thesubunits

dissociatefromGs;also,theGDPontheGsaisphosphorylatedtoGTP.

3 Gsa–GTPthencombineswithadenylatecyclasetoformtheactiveenzymethat

transformsATPintothesecondmessengercAMP.

4 Whenthesignalmoleculeonceagaindissociatesfromthereceptor,theGTP

boundtotheGsaisdephosphorylatedtoGDP,i.e.,inactivestatusisrestored.

Thisisthestepthatcholeratoxinprevents:theA 1 subunitofthecholeratoxin

(CTA 1 )catalyzesADP-ribosylationofGsa,whichthuslosesitsGTPaseactivityso

thattheadenylatecyclaseisnot“switchedoff”andsynthesisofcAMPcontinues

unchecked.

4

Kayser, Medical Microbiology © 2005 Thieme