Question

Mutations to proteins directly involved in the G-protein couple receptor could render the signaling pathway either constitutively active or inactive. Explain in which protein(s) can result in constitutively active signaling pathway and which one will result in inactive signaling by mutations.

Answer 1

GPCR have serpentine receptor ( Seven membrane spanning domains). In absence of signal molecule, hetrotrimeric G Protein complex is in inactive GDP form .On binding of signaling molecule , Confirmational change of receptor activates the G Protein Complex. This results from exchange of GDP with GTP.

Mutations that are constitutively active shows in increase in relevant signalling ( gain in function), the ones which are constitutively inactive shows decrease in relevant signalling ( Loss of Function) .

Examples that show constitutively activation and inactivation:-

1) In many GPCR , Asp(6.30) and Arg( 3.50 ) , Called Salt bridge or Ionic lock associated with activation or inhibition . Mutation of Asp (6.30 ) breaks the salt bridge,relieving the constraints and increasing the constitutional activity in several GPCR.

2) Melanocortin 4 receptor ( MC4R) involved in agonist binding ( Chemical that bind to receptor and activate the receptor) , it exhibits high basal activity,results in constitutional activation .Both presence of very high and low MC4R results in diseased condition.

3) Mutation also affects cell surface expression , for example - Any disruption of disulfide linkage between TM3 and extracellular side results in instability of receptor It shows constitutively inactivation mutation