Different chains for different gains : How acyl chain diversity shapes S-acylated protein function

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Busquets Hernández, Carla and Tsiotsia, Alexandra and Pipitò, Ludovico and Chamberlain, Luke H and Greaves, Jennifer and Triola, Gemma (2025) Different chains for different gains : How acyl chain diversity shapes S-acylated protein function. Progress in lipid research, 100. 101354. ISSN 1873-2194 (https://doi.org/10.1016/j.plipres.2025.101354)

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Abstract

S-Acylation is a critical post-translational modification involving the attachment of fatty acyl chains to a large and diverse array of soluble and membrane proteins. The last two decades have witnessed a substantial acceleration in our understanding of this process, fuelled by the discovery of acylation enzymes, mapping of the cellular S-acylome, and the development of new chemical biology methodologies to interrogate the mechanisms and functional outcomes of this lipid modification. This modification is often referred to as “S-Palmitoylation”, however mass spectrometry analyses have provided compelling evidence that the acyl chains added to S-acylated proteins are diverse, that site-specific attachment of different acyl chains can be seen, and that exogenous fatty acids can modulate the lipid profile of the S-acylome. This heterogeneity is likely generated through a combination of enzyme specificities, Acyl CoA distribution and availability, and specific features of the modified substrate protein. Despite a limited number of functional studies, acyl chain differences can impact protein localisation and function, and could possibly contribute to the development and progression of disease. It is now clear that recognising and understanding the functional consequences of acyl chain heterogeneity is a pivotal step toward a more complete view of lipid-mediated protein regulation.

ORCID iDs

Busquets Hernández, Carla, Tsiotsia, Alexandra, Pipitò, Ludovico, Chamberlain, Luke H ORCID logoORCID: https://orcid.org/0000-0002-8701-4995, Greaves, Jennifer and Triola, Gemma;
CORE (COnnecting REpositories)