Proteomics

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Structural mechanism underlying primary and secondary coupling between GPCRs and the Gi/o family


ABSTRACT: G protein-coupled receptors (GPCRs) are the largest receptor superfamily that can propagate various extracellular stimulus into cells by coupling with heterotrimeric G proteins. G proteins are divided into four families, Gs, Gi/o, Gq/11 and G12/13, which are responsible for the transduction of discrete downstream signaling pathways. Interestingly, one receptor can couple to more than one G protein subtype with different coupling efficiency or kinetics; coupling with the highest efficiency and/or kinetics is known as ‘primary coupling’ whereas the one with lower efficiency and/or slower kinetics is known as ‘secondary coupling’. Due to its significance in human physiology, there has been a great effort to elucidate the precise mechanism of GPCR-G protein coupling, however, the complex nature of GPCR and G protein interaction raises more unanswered questions. Here, we utilized hydrogen/deuterium exchange mass spectrometry (HDX-MS) to understand the molecular mechanism underlying primary and secondary Gi/o coupling using muscarinic acetylcholine receptor type 2 (M2R) and β2-adrenergic receptor (β2AR) as the primary and secondary Gi/o-coupling receptors, respectively. Results showed the engagement of the distal C-terminus of Gi/o with the receptor differentiates primary and secondary Gi/o couplings. In addition, the interaction between the intracellular loop 2 (ICL2) of the receptor and Gi/o in primary Gi/o coupling is not as critical as in primary Gs coupling.

INSTRUMENT(S): Xevo G2 Q-Tof

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Hee Ryung Kim  

LAB HEAD: Ka Young Chung

PROVIDER: PXD019367 | Pride | 2020-07-02

REPOSITORIES: Pride

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Structural mechanism underlying primary and secondary coupling between GPCRs and the Gi/o family.

Kim Hee Ryung HR   Xu Jun J   Maeda Shoji S   Duc Nguyen Minh NM   Ahn Donghoon D   Du Yang Y   Chung Ka Young KY  

Nature communications 20200622 1


Heterotrimeric G proteins are categorized into four main families based on their function and sequence, Gs, Gi/o, Gq/11, and G12/13. One receptor can couple to more than one G protein subtype, and the coupling efficiency varies depending on the GPCR-G protein pair. However, the precise mechanism underlying different coupling efficiencies is unknown. Here, we study the structural mechanism underlying primary and secondary Gi/o coupling, using the muscarinic acetylcholine receptor type 2 (M2R) as  ...[more]

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