Computational model of the full-length TSH receptor

  1. Mihaly Mezei  Is a corresponding author
  2. Rauf Latif
  3. Terry F Davies
  1. Icahn School of Medicine at Mount Sinai, United States

Abstract

The receptor for thyroid stimulating hormone (TSHR), a GPCR, is of particular interest as the primary antigen in autoimmune hyperthyroidism (Graves' disease) caused by stimulating TSHR antibodies. To date, only one domain of the extracellular region of the TSHR has been crystallized. We have run a 1000ns Molecular Dynamic simulation on a model of the entire TSHR generated by merging the extracellular region of the receptor, obtained using artificial intelligence, with our recent homology model of the transmembrane domain, embedded it in a lipid membrane solvated it with water and counterions. The simulations showed that the structure of the transmembrane and leucine-rich domains were remarkably constant while the linking region (LR), known more commonly as the 'hinge region', showed significant flexibility, forming several transient secondary structural elements. Furthermore, the relative orientation of the leucine-rich domain with the rest of the receptor was also seen to be variable. These data suggest that this linker region is an intrinsically disordered protein (IDP). Furthermore, preliminary data simulating the full TSHR model complexed with its ligand (TSH) showed that (a) there is a strong affinity between the linker region and TSH ligand and (b) the association of the linker region and the TSH ligand reduces the structural fluctuations in the linker region. This full-length model illustrates the importance of the linker region in responding to ligand binding and lays the foundation for studies of pathologic TSHR autoantibodies complexed with the TSHR to give further insight into their interaction with the flexible linker region.

Data availability

The initial model generated is available from the Dryad server; URL: https://doi.org/10.5061/dryad.rjdfn2zdp.The software used for the analysis are available at the URL https://mezeim01.u.hpc.mssm.edu

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Mihaly Mezei

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    For correspondence
    Mihaly.Mezei@mssm.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0294-4307
  2. Rauf Latif

    Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4226-3728
  3. Terry F Davies

    Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    Terry F Davies, is member of the Board of Kronus Inc (Starr, ID, USA); MM, and RF have nothing to disclose..

Funding

NIH Office of the Director (DK069713)

  • Mihaly Mezei

Veterans Administration merit award (BX000800)

  • Terry F Davies

Segal Family Foundation (00000000)

  • Terry F Davies

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Mezei et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Mihaly Mezei
  2. Rauf Latif
  3. Terry F Davies
(2022)
Computational model of the full-length TSH receptor
eLife 11:e81415.
https://doi.org/10.7554/eLife.81415

Share this article

https://doi.org/10.7554/eLife.81415

Further reading

    1. Immunology and Inflammation
    2. Structural Biology and Molecular Biophysics
    Colleen A Maillie, Kiana Golden ... Marco Mravic
    Research Article

    A potent class of HIV-1 broadly neutralizing antibodies (bnAbs) targets the envelope glycoprotein’s membrane proximal exposed region (MPER) through a proposed mechanism where hypervariable loops embed into lipid bilayers and engage headgroup moieties alongside the epitope. We address the feasibility and determinant molecular features of this mechanism using multi-scale modeling. All-atom simulations of 4E10, PGZL1, 10E8, and LN01 docked onto HIV-like membranes consistently form phospholipid complexes at key complementarity-determining region loop sites, solidifying that stable and specific lipid interactions anchor bnAbs to membrane surfaces. Ancillary protein-lipid contacts reveal surprising contributions from antibody framework regions. Coarse-grained simulations effectively capture antibodies embedding into membranes. Simulations estimating protein-membrane interaction strength for PGZL1 variants along an inferred maturation pathway show bilayer affinity is evolved and correlates with neutralization potency. The modeling demonstrated here uncovers insights into lipid participation in antibodies’ recognition of membrane proteins and highlights antibody features to prioritize in vaccine design.

    1. Immunology and Inflammation
    2. Structural Biology and Molecular Biophysics
    Ana Cristina Chang-Gonzalez, Aoi Akitsu ... Wonmuk Hwang
    Research Advance

    Increasing evidence suggests that mechanical load on the αβ T-cell receptor (TCR) is crucial for recognizing the antigenic peptide-bound major histocompatibility complex (pMHC) molecule. Our recent all-atom molecular dynamics (MD) simulations revealed that the inter-domain motion of the TCR is responsible for the load-induced catch bond behavior of the TCR-pMHC complex and peptide discrimination (Chang-Gonzalez et al., 2024). To further examine the generality of the mechanism, we perform all-atom MD simulations of the B7 TCR under different conditions for comparison with our previous simulations of the A6 TCR. The two TCRs recognize the same pMHC and have similar interfaces with pMHC in crystal structures. We find that the B7 TCR-pMHC interface stabilizes under ∼15 pN load using a conserved dynamic allostery mechanism that involves the asymmetric motion of the TCR chassis. However, despite forming comparable contacts with pMHC as A6 in the crystal structure, B7 has fewer high-occupancy contacts with pMHC and exhibits higher mechanical compliance during the simulation. These results indicate that the dynamic allostery common to the TCRαβ chassis can amplify slight differences in interfacial contacts into distinctive mechanical responses and nuanced biological outcomes.