Proximity-enhanced cysteine-histidine crosslinking for elucidating intrinsically disordered and other protein complexes.

ABSTRACT: Disordered proteins and domains are ubiquitous throughout the proteome of human cell types, yet the biomolecular sciences lack effective tool compounds and chemical strategies to study this class of proteins. In this context, we introduce a novel covalent tool compound approach that combines proximity-enhanced crosslinking with histidine trapping. Utilizing a maleimide-cyclohexenone crosslinker for efficient cysteine-histidine crosslinking, we elucidated the mechanism of this dual-reactive tool compound class. This tool compound concept was then applied to profile the full-length complex of 14-3-3 and hyperphosphorylated Tau (hpTau), relevant to Alzheimer's. This approach identified a cryptic binding interaction between 14-3-3 and hpTau via its phosphorylated Ser356, overlooked by t

SUBMITTER: Wu Q 

PROVIDER: S-EPMC11752056 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature