Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors.

Journal Article (Journal Article)

Mammalian odorant receptors are a diverse and rapidly evolving set of G protein-coupled receptors expressed in olfactory cilia membranes. Most odorant receptors show little to no cell surface expression in nonolfactory cells due to endoplasmic reticulum retention, which has slowed down biochemical studies. Here we provide evidence that structural instability and divergence from conserved residues of individual odorant receptors underlie intracellular retention using a combination of large-scale screening of odorant receptors cell surface expression in heterologous cells, point mutations, structural modeling, and machine learning techniques. We demonstrate the importance of conserved residues by synthesizing consensus odorant receptors that show high levels of cell surface expression similar to conventional G protein-coupled receptors. Furthermore, we associate in silico structural instability with poor cell surface expression using molecular dynamics simulations. We propose an enhanced evolutionary capacitance of olfactory sensory neurons that enable the functional expression of odorant receptors with cryptic mutations.

Full Text

Duke Authors

Cited Authors

  • Ikegami, K; de March, CA; Nagai, MH; Ghosh, S; Do, M; Sharma, R; Bruguera, ES; Lu, YE; Fukutani, Y; Vaidehi, N; Yohda, M; Matsunami, H

Published Date

  • February 11, 2020

Published In

Volume / Issue

  • 117 / 6

Start / End Page

  • 2957 - 2967

PubMed ID

  • 31974307

Pubmed Central ID

  • PMC7022149

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1915520117


  • eng

Conference Location

  • United States