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PreprintCited by 3Growth Hormone and Insulin-like Growth FactorsReceptor Mechanisms and SignalingMetabolism, Diabetes, and Cancer

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Using site-directed mutagenesis to further the understanding of insulin receptor-insulin like growth factor-1 receptor heterodimer structure

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Turvey, Samuel, Muench, Stephen P, Issad, Tarik, Fishwick, Colin WG, Kearney, Mark T, Simmons, Katie J·2024·Growth Hormone & IGF Research
DOI 10.1101/2024.03.05.583490

Preprint — published as 10.1016/j.ghir.2024.101607 · Paper page

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Abstract

Type 2 diabetes is characterised by the disruption of insulin and insulin-like growth factor (IGF) signalling. The key hubs of these signalling cascades - the Insulin receptor (IR) and Insulin-like growth factor 1 receptor (IGF1R) – are known to form functional IR-IGF1R hybrid receptors which are insulin resistant. However, the mechanisms underpinning IR-IGF1R hybrid formation are not fully understood, hindering the ability to modulate this for future therapies targeting this receptor. To pinpoint suitable sites for intervention, computational hotspot prediction was utilised to identify promising epitopes for targeting with point mutagenesis. Specific IGF1R point mutations F450A, R391A and D555A show reduced affinity of the hybrid receptor in a BRET based donor-saturation assay, confirming hybrid formation could be modulated at this interface. These data provide the basis for rational design of more effective hybrid receptor modulators, supporting the prospect of identifying a small molecule that specifically interacts with this target.

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Metadata

Authors
Turvey, S., Muench, S. P., Issad, T., Fishwick, C. W., Kearney, M. T., & Simmons, K. J.
Affiliations
  • University of Leeds (GB)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Simmons, Katie J
ORCID
Venue
Growth Hormone & IGF Research
Publisher
openRxiv
Published
2024-03-08
Volume
77
Pages
101607-101607
ISSN
1096-6374 (ISSN-L)
DOI
10.1101/2024.03.05.583490
OpenAlex
W4400766437
Cited by
3
References
1
Citations by year
2026: 1 · 2025: 2
FWCI
0.99
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Growth Hormone & IGF Research (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
Funders
British Heart Foundation (FS/19/59/34896)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
insulin receptor, IGF-1 receptor, receptor heterodimerization, type 2 diabetes, insulin resistance, site-directed mutagenesis, small molecule modulators
MeSH terms
Insulin-Like Peptides, Humans, Receptor, Insulin, Antigens, CD, Mutagenesis, Site-Directed, Receptor, IGF Type 1, Protein Multimerization

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