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Impact of secretin receptor homo-dimerization on natural ligand binding

Author

Listed:
  • Kaleeckal G. Harikumar

    (Mayo Clinic)

  • Sarah J. Piper

    (Monash University
    Monash University)

  • Arthur Christopoulos

    (Monash University
    Monash University)

  • Denise Wootten

    (Monash University
    Monash University)

  • Patrick M. Sexton

    (Monash University
    Monash University)

  • Laurence J. Miller

    (Mayo Clinic)

Abstract

Class B G protein-coupled receptors can form dimeric complexes important for high potency biological effects. Here, we apply pharmacological, biochemical, and biophysical techniques to cells and membranes expressing the prototypic secretin receptor (SecR) to gain insights into secretin binding to homo-dimeric and monomeric SecR. Spatial proximity between peptide and receptor residues, probed by disulfide bond formation, demonstrates that the secretin N-terminus moves from adjacent to extracellular loop 3 (ECL3) at wild type SecR toward ECL2 in non-dimerizing mutants. Analysis of fluorescent secretin analogs demonstrates stable engagement of the secretin C-terminal region within the receptor extracellular domain (ECD) for both dimeric and monomeric receptors, while the mid-region exhibits lower mobility while docked at the monomer. Moreover, decoupling of G protein interaction reduces mobility of the peptide mid-region at wild type receptor to levels similar to the mutant, whereas it has no further impact on the monomer. These data support a model of peptide engagement whereby the ability of SecR to dimerize promotes higher conformational dynamics of the peptide-bound receptor ECD and ECLs that likely facilitates more efficient G protein recruitment and activation, consistent with the higher observed functional potency of secretin at wild type SecR relative to the monomeric mutant receptor.

Suggested Citation

  • Kaleeckal G. Harikumar & Sarah J. Piper & Arthur Christopoulos & Denise Wootten & Patrick M. Sexton & Laurence J. Miller, 2024. "Impact of secretin receptor homo-dimerization on natural ligand binding," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48853-6
    DOI: 10.1038/s41467-024-48853-6
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    1. Yi-Lynn Liang & Maryam Khoshouei & Alisa Glukhova & Sebastian G. B. Furness & Peishen Zhao & Lachlan Clydesdale & Cassandra Koole & Tin T. Truong & David M. Thal & Saifei Lei & Mazdak Radjainia & Rado, 2018. "Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor–Gs complex," Nature, Nature, vol. 555(7694), pages 121-125, March.
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    3. Yi-Lynn Liang & Maryam Khoshouei & Giuseppe Deganutti & Alisa Glukhova & Cassandra Koole & Thomas S. Peat & Mazdak Radjainia & Jürgen M. Plitzko & Wolfgang Baumeister & Laurence J. Miller & Deborah L., 2018. "Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor," Nature, Nature, vol. 561(7724), pages 492-497, September.
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