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

Author(s):Show less -

Ikegami, Kentaro ^{[1, 2]} ; de March, Claire A. ^[1] ; Nagai, Maira H. ^{[3, 1]} ; Ghosh, Soumadwip ^[4] ; Do, Matthew ^[1] ; Sharma, Ruchira ^[1] ; Bruguera, Elise S. ^[1] ; Lu, Yueyang Eric ^[1] ; Fukutani, Yosuke ^{[1, 2]} ; Vaidehi, Nagarajan ^[4] ; Yohda, Masafumi ^[2] ; Matsunami, Hiroaki ^{[1, 5]}

Affiliation

^[1] Duke Univ, Sch Med, Dept Mol Genet & Microbiol, Durham, NC 27710 - USA

^[2] Tokyo Univ Agr & Technol, Dept Biotechnol & Life Sci, Tokyo 1848588 - Japan

^[3] Univ Sao Paulo, Dept Biochem, BR-05508000 Sao Paulo - Brazil

^[4] City Hope Natl Med Ctr, Beckman Res Inst, Dept Computat & Quantitat Med, Duarte, CA 91010 - USA

^[5] Duke Univ, Duke Inst Brain Sci, Dept Neurobiol, Durham, NC 27710 - USA

• Document type: Journal article
• Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 117, n. 6, p. 2957-2967, FEB 11 2020.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 17/00726-2 - Study of Ric-8B's function in mTOR activation by using an olfactory model
• Grantee: Maíra Harume Nagai
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor