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Characterizing glucokinase variant mechanisms using a multiplexed abundance assay

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Gersing, Sarah, Schulze, Thea K., Cagiada, Matteo, Stein, Amelie, Roth, Frederick P., Lindorff-Larsen, Kresten, Hartmann-Petersen, Rasmus·2024·Genome Biology
DOI 10.1186/s13059-024-03238-2PMC PMC11021015

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Abstract

Background: Amino acid substitutions can perturb protein activity in multiple ways. Understanding their mechanistic basis may pinpoint how residues contribute to protein function. Here, we characterize the mechanisms underlying variant effects in human glucokinase (GCK) variants, building on our previous comprehensive study on GCK variant activity. Results: Using a yeast growth-based assay, we score the abundance of 95% of GCK missense and nonsense variants. When combining the abundance scores with our previously determined activity scores, we find that 43% of hypoactive variants also decrease cellular protein abundance. The low-abundance variants are enriched in the large domain, while residues in the small domain are tolerant to mutations with respect to abundance. Instead, many variants in the small domain perturb GCK conformational dynamics which are essential for appropriate activity. Conclusions: In this study, we identify residues important for GCK metabolic stability and conformational dynamics. These residues could be targeted to modulate GCK activity, and thereby affect glucose homeostasis.

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  • For GCK, the effects of nearly all possible missense and nonsense variants on enzyme activity and protein abundance have been studied in yeast complementation-based MAVEs.

    “examples of notable progress are seen for monogenic diabetes genes glucokinase (GCK), for which the effects of nearly all possible missense and nonsense variants on enzyme activity and protein abundance have been studied in yeast complementation-based MAVEs (114, 115)”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [114]

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  75. [78]Gersing S Schulze TK Cagiada M Stein A Roth FP Lindorff-Larsen K Characterizing glucokinase variant mechanisms using a multiplexed abundance assay Zenodo 2024 10.5281/zenodo.10837281 PMC11021015 38627865 · DOI

Cited by

Sorted by citations

Authors
Gersing, S., Schulze, T. K., Cagiada, M., Stein, A., Roth, F. P., Lindorff-Larsen, K., & Hartmann-Petersen, R.
Affiliations
  • University of Copenhagen (DK)
  • University of Toronto (CA)
Corresponding author
Gersing, Sarah
ORCID
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2024-04-16
Volume
25
Issue
1
Pages
98-98
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/s13059-024-03238-2
PMC
PMC11021015
OpenAlex
W4394847708
Cited by
23
References
2
Citations by year
2026: 11 · 2025: 6 · 2024: 5 · 2023: 1
FWCI
8.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Novo Nordisk Fonden (PRISM NNF18OC0033950, REPIN NNF18OC0033926, ROBUST NF18OC0032608)
  • Natur og Univers, Det Frie Forskningsråd (10.46540/2032-00007B)
  • National Institutes of Health (Human Genome Research Institute (NIH/NHGRI) Center of Excellence in Genomic Science Initiative (HG010461))
  • NIH/NHGRI (Impact of Genomic Variation on Function (IGVF) Initiative (HG011989))
  • Canadian Institutes of Health Research (Foundation Grant)
  • Copenhagen University
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
glucokinase, missense mutations, nonsense mutation, protein abundance, protein stability, conformational dynamics, amino acid substitutions, glucose homeostasis, metabolic stability

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