9f35
Co-crystal structure of 14-3-3sigma in complex with B-Raf pS365 phosphopeptide
Structural highlights
Function1433S_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression. Publication Abstract from PubMedDisordered 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 the majority of 14-3-3/Tau literature. Utilizing a mutational study and an equilibrium model, this cryptic binding interaction is revealed to play a prominent biomolecular role at cellularly relevant concentrations. This finding necessitates a re-evaluation of the mechanism of the 14-3-3/Tau interaction. The histidine-trap crosslinker approach reported here not only advances our understanding of the 14-3-3/Tau interaction but also demonstrates the potential of dual-covalent tool compounds in studying complex interactions involving IDPs and IDDs. Proximity-enhanced cysteine-histidine crosslinking for elucidating intrinsically disordered and other protein complexes.,Wu Q, van den Wildenberg SAH, Brzoskowski JCR, van den Oetelaar MCM, Verhoef CJA, Genet SAAM, Ottmann C, Markvoort AJ, Brunsveld L, Cossar PJ Chem Sci. 2025 Jan 7. doi: 10.1039/d4sc07419j. PMID:39850253[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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