The dynamic addition and removal of long-chain fatty acids modulate protein function and localization. The α/β hydrolase domain–containing (ABHD) 17 enzymes remove acyl chains from membrane-localized proteins such as the oncoprotein NRas, but how the ABHD17 proteins are regulated is unknown. Here, we used cell-based studies and molecular dynamics simulations to show that ABHD17 activity is controlled by two mobile elements—an S-acylated N-terminal helix and a loop—that flank the putative substrate-binding pocket. Multiple S-acylation events anchor the N-terminal helix in the membrane, enabling hydrophobic residues in the loop to engage with the bilayer. This stabilizes the conformation of both helix and loop, alters the conformation of the binding pocket, and optimally positions the enzyme for substrate engagement. S-acylation may be a general feature of acyl-protein thioesterases. By providing a mechanistic understanding of how the lipid modification of a lipid-removing enzyme promotes its enzymatic activity, this work contributes to our understanding of cellular S-acylation cycles.
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February 14 2025
An S-acylated N-terminus and a conserved loop regulate the activity of the ABHD17 deacylase
Sydney Holme
,
Sydney Holme
*
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Writing - original draft)
1Department of Medical Genetics,
University of British Columbia
, Vancouver, BC, Canada
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Jennifer Sapia
,
Jennifer Sapia
*
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing)
3Department of Biology,
University of Fribourg
, Fribourg, Switzerland
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Michael Davey
,
Michael Davey
(Investigation, Methodology, Resources)
2
Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital Research Institute, University of British Columbia
, Vancouver, BC, Canada
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Stefano Vanni
,
(Conceptualization, Formal analysis, Funding acquisition, Resources, Supervision, Writing - original draft, Writing - review & editing)
3Department of Biology,
University of Fribourg
, Fribourg, Switzerland
Stefano Vanni: [email protected]
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Elizabeth Conibear
(Conceptualization, Data curation, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing)
1Department of Medical Genetics,
University of British Columbia
, Vancouver, BC, Canada
Correspondence to Elizabeth Conibear: [email protected]
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Sydney Holme
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Writing - original draft
*
1Department of Medical Genetics,
University of British Columbia
, Vancouver, BC, Canada
Jennifer Sapia
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
*
3Department of Biology,
University of Fribourg
, Fribourg, Switzerland
Michael Davey
Investigation, Methodology, Resources
2
Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital Research Institute, University of British Columbia
, Vancouver, BC, Canada
Stefano Vanni
Conceptualization, Formal analysis, Funding acquisition, Resources, Supervision, Writing - original draft, Writing - review & editing
3Department of Biology,
University of Fribourg
, Fribourg, Switzerland
Correspondence to Elizabeth Conibear: [email protected]
Stefano Vanni: [email protected]
*
S. Holme and J. Sapia contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
May 14 2024
Revision Received:
December 07 2024
Accepted:
January 22 2025
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
Canada Foundation for Innovation
- Award Id(s): 30636
Funder(s):
Canadian Institutes of Health Research
- Award Id(s): 162184
Funder(s):
European Research Council
- Award Id(s): 803952
Funder(s):
Swiss National Supercomputing Centre
- Award Id(s): s1132,s1176,s1221
© 2025 Holme et al.
2025
Holme et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Cell Biol (2025) 224 (4): e202405042.
Article history
Received:
May 14 2024
Revision Received:
December 07 2024
Accepted:
January 22 2025
Citation
Sydney Holme, Jennifer Sapia, Michael Davey, Stefano Vanni, Elizabeth Conibear; An S-acylated N-terminus and a conserved loop regulate the activity of the ABHD17 deacylase. J Cell Biol 3 April 2025; 224 (4): e202405042. doi: https://doi.org/10.1083/jcb.202405042
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