Conformational editing of intrinsically disordered protein by α-methylation.

Date publication

novembre 2020

Journal

Chemical science

Auteurs

Membres identifiés du Cancéropôle Est :
Dr KIEFFER Bruno , Dr ROCHEL-GUIBERTEAU Natacha , Dr TRAVE Gilles , Dr NOMINE Yves , Dr OSZ-PAPAI Judit , Dr GOGL Gergo

Tous les auteurs :
Bauer V, Schmidtgall B, Gógl G, Dolenc J, Osz J, Nominé Y, Kostmann C, Cousido-Siah A, Mitschler A, Rochel N, Travé G, Kieffer B, Torbeev V

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/34163874

Résumé

Intrinsically disordered proteins (IDPs) constitute a large portion of "Dark Proteome" - difficult to characterize or yet to be discovered protein structures. Here we used conformationally constrained α-methylated amino acids to bias the conformational ensemble in the free unstructured activation domain of transcriptional coactivator ACTR. Different sites and patterns of substitutions were enabled by chemical protein synthesis and led to distinct populations of α-helices. A specific substitution pattern resulted in a substantially higher binding affinity to nuclear coactivator binding domain (NCBD) of CREB-binding protein, a natural binding partner of ACTR. The first X-ray structure of the modified ACTR domain - NCBD complex visualized a unique conformation of ACTR and confirmed that the key α-methylated amino acids are localized within α-helices in the bound state. This study demonstrates a strategy for characterization of individual conformational states of IDPs.

Référence

Chem Sci. 2020 Nov 4;12(3):1080-1089