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Isomer-Resolved Enzyme-Centric Chemoproteomics Reveals Structure-Specific Fatty Acid S-Acylation Modification Networks

ABSTRACT: Protein lipidation is a critical post-translational modification, but the relationship between the fine structure of fatty acids (FAs) and the specificity of lipidation remains largely unexplored. Here, we developed an isomer-resolved enzyme-centered chemoproteomic strategy to elucidate the intricate relationships between the key players involved in the lipidation modification process. By synthesizing alkyne-tagged FA isomer probes in combination with zDHHC enzyme overexpression and quantitative proteomics, we revealed at the proteomic level how minor isomeric differences in FAs affect their modification. Protein lipidation was shown to have a marked specificity for the C=C bond isomerism, and the comprehensive network between FA isomers, zDHHC enzymes, and S-acylated proteins was mapped. Furthermore, the isomeric selectivity and the spatial binding characteristics of autoacylation intermediates were elucidated, suggesting the molecular determinants governing this specificity. This study provides deep insights into the molecular basis of protein lipidation modification.

ORGANISM(S): Homo Sapiens

SUBMITTER: Suming Chen

PROVIDER: PXD074124 | iProX | Fri Feb 06 00:00:00 GMT 2026

REPOSITORIES: iProX

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