Lessons from constitutively active mutants of G protein-coupled receptors.
In the past decade, the concept of constitutive activity has profoundly modified our understanding of G protein-coupled-receptors (GPCRs). Here, we review the contribution of constitutively active mutants (CAMs) to our understanding of three aspects of GPCR physiopathology: (1) GPCR activation is a complex mechanism involving both the release of inactive state conformational constraints, mimicked by most CAMs, and the creation of new interactions that stabilize the active state and are mimicked by a restricted set of CAMs; (2) GPCR phosphorylation, internalization and desensitization processes are activated by receptor conformations, which partly overlap those activating G protein; (3) natural CAMs, mostly affecting GPCRs of the endocrine system, are found in several hereditary and acquired diseases, including cancers. One major remaining question is how CAMs recapitulate the different structural modifications of the agonist-induced active conformation(s) of the wild-type receptor. This characterization is a prerequisite for further use of CAMs as ligand-free models of active GPCRs in structural, cellular and physiological studies.
Parnot
Charles
C
INSERM U567, CNRS UMR8104, Institut Cochin, Faculté de Médecine Cochin, 24 rue du Fg St Jacques, F-75014 Paris, France.
Miserey-Lenkei
Stéphanie
S
Bardin
Sabine
S
Corvol
Pierre
P
Clauser
Eric
E
D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins / Q000737:chemistry; D019204:GTP-Binding Proteins; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D044140:Receptor, Angiotensin, Type 1; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D011945:Receptors, Angiotensin / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D011989:Receptors, Thyrotropin / Q000737:chemistry; D012097:Repressor Proteins / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000737:chemistry
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D044140:Receptor, Angiotensin, Type 1; D018343:Receptors, Adrenergic, beta-2; D011945:Receptors, Angiotensin; D011956:Receptors, Cell Surface; D011989:Receptors, Thyrotropin; D012097:Repressor Proteins; D019204:GTP-Binding Proteins