Abstract
Pentameric ligand-gated ion channels (PLGICs) are a family of proteins that convert chemical signals into ion fluxes through cellular membranes. Their structures are highly conserved across all kingdoms from bacteria to eukaryotes. Beyond their classical roles in neurotransmission and neurological disorders, PLGICs have been recently related to cell proliferation and cancer. Here, we focus on the best characterized eukaryotic channel, the glycine receptor (GlyR), to investigate its mutational patterns in genomic-wide tumor screens and compare them with mutations linked to hyperekplexia (HPX), a Mendelian neuromotor disease that disrupts glycinergic currents. Our analysis highlights that cancer mutations significantly accumulate across TM1 and TM2, partially overlapping with HPX changes. Based on 3D-clustering, conservation, and phenotypic data, we select three mutations near the pore, expected to impact GlyR conformation, for further study by molecular dynamics (MD). Using principal components from experimental GlyR ensembles as framework, we explore the motions involved in transitions from the human closed and desensitized structures and how they are perturbed by mutations. Our MD simulations show that WT GlyR spontaneously explores opening and re-sensitization transitions that are significantly impaired by mutations, resulting in receptors with altered permeability and desensitization properties in agreement with HPX functional data.
Original language | English |
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Article number | 890851 |
Journal | Frontiers in Molecular Biosciences |
Volume | 9 |
DOIs | |
State | Published - 28 Jun 2022 |
Externally published | Yes |
Bibliographical note
Funding Information:This work was supported by Cancerfonden Junior Investigator Award (21 0305 JIA 01 H) and Project Grant (CF 21 1471 Pj 2022-24), Jeanssons Foundation 2021, Vetenskapsrådet Starting Grant VR2021-02248 2022-25, and Karolinska Institute KIS, KIF Grants to LO. Simulations were run using the Swedish National Infrastructure for Computing (allocations Q13 SNIC 2021/5-87 and 2021/5-409 to LO).
Funding Information:
LO thanks the Swedish Cancer Foundation (Cancerfonden), the Swedish Research Council (Vetenskapsrådet), the Jeanssons Foundation (Harald och Greta Jeanssons Stiftelse) and Karolinska Institute for generous support.
Funding Information:
This work was supported by Cancerfonden Junior Investigator Award (21 0305 JIA 01 H) and Project Grant (CF 21 1471 Pj 2022-24), Jeanssons Foundation 2021, Vetenskapsrådet Starting Grant VR2021-02248 2022-25, and Karolinska Institute KIS, KIF Grants to LO. Simulations were run using the Swedish National Infrastructure for Computing (allocations Q13 SNIC 2021/5-87 and 2021/5-409 to LO).
Publisher Copyright:
Copyright © 2022 Mhashal, Yoluk and Orellana.
Keywords
- cancer
- coarse-grained (CG) methods
- glycine receptor (GlyR)
- hyperekplexia
- molecular dynamics
- mutations