Extramembranous Regions in G Protein-Coupled Receptors: Cinderella in Receptor Biology?
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G protein-coupled receptors (GPCRs) are the largest class of membrane proteins involved in signal transduction and are characterized by seven transmembrane domain architecture interconnected by extra- and intracellular loops. These loops, along with the N- and C-terminal domains, constitute the extramembranous regions in GPCRs. These regions, accounting for ~ 40% or more amino acid residues across different GPCR classes, are distinct from the conserved transmembrane domains in terms of nonconservation of sequence, diversity in length, and conformational heterogeneity. Due to technical challenges in exploring the molecular basis underlying the relation between structure, dynamics, and function in these regions, their contribution to GPCR organization and signaling remain underappreciated. Despite existing literature on the involvement of GPCR loops in numerous aspects of GPCR biology, the functional relevance of GPCR loops in the context of their inherent conformational heterogeneity and probable membrane interaction are not well understood. This review focuses on highlighting these aspects of GPCR extramembranous regions in the overall context of GPCR organization, dynamics, and biology. We envision that a judicious combination of insights obtained from structured transmembrane domains and disordered extramembranous regions in GPCRs would be crucial in arriving at a comprehensive understanding of GPCR structure, function, and dynamics, thereby leading to efficient drug discovery.
KeywordsGPCR GPCR extramembranous regions Conformational heterogeneity Intrinsically disordered regions in GPCRs Membrane interaction of GPCR loops
A.C. gratefully acknowledges support from SERB Distinguished Fellowship (Department of Science and Technology, Govt. of India). S.P. thanks the University Grants Commission for the award of a Senior Research Fellowship. A.C. is a Distinguished Visiting Professor at the Indian Institute of Technology (Bombay); Adjunct Professor at the Tata Institute of Fundamental Research (Mumbai), the RMIT University (Melbourne, Australia), and the Indian Institute of Science Education and Research (Kolkata); and an Honorary Professor at the Jawaharlal Nehru Centre for Advanced Scientific Research (Bengaluru). We thank members of the Chattopadhyay laboratory, Parijat Sarkar in particular, for comments and discussions.
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Conflict of interest
The authors declare that they have no conflicts of interest.
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