Extramembranous Regions in G Protein-Coupled Receptors: Cinderella in Receptor Biology?
- PMID:31471645
- DOI: 10.1007/s00232-019-00092-3
Extramembranous Regions in G Protein-Coupled Receptors: Cinderella in Receptor Biology?
Abstract
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.
Keywords: Conformational heterogeneity; GPCR; GPCR extramembranous regions; Intrinsically disordered regions in GPCRs; Membrane interaction of GPCR loops.
Similar articles
- 7TM Domain Structure of Adhesion GPCRs.de Graaf C, Nijmeijer S, Wolf S, Ernst OP.de Graaf C, et al.Handb Exp Pharmacol. 2016;234:43-66. doi: 10.1007/978-3-319-41523-9_3.Handb Exp Pharmacol. 2016.PMID:27832483Review.
- Structure-Based Sequence Alignment of the Transmembrane Domains of All Human GPCRs: Phylogenetic, Structural and Functional Implications.Cvicek V, Goddard WA 3rd, Abrol R.Cvicek V, et al.PLoS Comput Biol. 2016 Mar 30;12(3):e1004805. doi: 10.1371/journal.pcbi.1004805. eCollection 2016 Mar.PLoS Comput Biol. 2016.PMID:27028541Free PMC article.
- Structural biology of G protein-coupled receptor signaling complexes.Edward Zhou X, Melcher K, Eric Xu H.Edward Zhou X, et al.Protein Sci. 2019 Mar;28(3):487-501. doi: 10.1002/pro.3526. Epub 2018 Dec 13.Protein Sci. 2019.PMID:30311978Free PMC article.Review.
- G protein-coupled receptors show unusual patterns of intrinsic unfolding.Jaakola VP, Prilusky J, Sussman JL, Goldman A.Jaakola VP, et al.Protein Eng Des Sel. 2005 Feb;18(2):103-10. doi: 10.1093/protein/gzi004. Epub 2005 Mar 24.Protein Eng Des Sel. 2005.PMID:15790574
- Structured and disordered facets of the GPCR fold.Venkatakrishnan AJ, Flock T, Prado DE, Oates ME, Gough J, Madan Babu M.Venkatakrishnan AJ, et al.Curr Opin Struct Biol. 2014 Aug;27:129-37. doi: 10.1016/j.sbi.2014.08.002. Epub 2014 Sep 3.Curr Opin Struct Biol. 2014.PMID:25198166Review.
Cited by
- Lysine 101 in the CRAC Motif in Transmembrane Helix 2 Confers Cholesterol-Induced Thermal Stability to the Serotonin1A Receptor.Sarkar P, Bhat A, Chattopadhyay A.Sarkar P, et al.J Membr Biol. 2022 Dec;255(6):739-746. doi: 10.1007/s00232-022-00262-w. Epub 2022 Aug 20.J Membr Biol. 2022.PMID:35986776
- Cholesterol in GPCR Structures: Prevalence and Relevance.Sarkar P, Chattopadhyay A.Sarkar P, et al.J Membr Biol. 2022 Feb;255(1):99-106. doi: 10.1007/s00232-021-00197-8. Epub 2021 Aug 7.J Membr Biol. 2022.PMID:34365520
- A molecular sensor for cholesterol in the human serotonin1A receptor.Kumar GA, Sarkar P, Stepniewski TM, Jafurulla M, Singh SP, Selent J, Chattopadhyay A.Kumar GA, et al.Sci Adv. 2021 Jul 23;7(30):eabh2922. doi: 10.1126/sciadv.abh2922. Print 2021 Jul.Sci Adv. 2021.PMID:34301606Free PMC article.
- Non-canonical helical transitions and conformational switching are associated with characteristic flexibility and disorder indices in TRP and Kv channels.García-Morales A, Balleza D.García-Morales A, et al.Channels (Austin). 2023 Dec;17(1):2212349. doi: 10.1080/19336950.2023.2212349.Channels (Austin). 2023.PMID:37196183Free PMC article.
- Special Issue: Membrane and Receptor Dynamics.Prakash S, Sengupta D.Prakash S, et al.J Membr Biol. 2019 Oct;252(4-5):207-211. doi: 10.1007/s00232-019-00096-z.J Membr Biol. 2019.PMID:31583440No abstract available.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources