Molecular Insights into Selective Recognition of Phosphorylated Linear Peptide Motifs by Tandem BRCT Domains

Abstract

Tandem BRCT (tBRCT) domains are reader domains that transduce phosphorylation-dependent signaling initiated by kinases.tBRCT domains recognize linear peptide motifs containing Serine/Threonine on partner proteins only upon their phosphorylation. The two BRCT domains that are juxtaposed in parallel bind phosphopeptides via phosphoserine (pS) or phophothreonine (pT) in such a way that the phosphopeptide’s pS/pT (0 position residue) contacts the N-BRCT, while the +3/+4 residue engages a hydrophobic pocket at the interface of N- and C-BRCTs. We studied various tBRCT domain-containing proteins, BRCA1, MCPH1, TopBP1, MDC1 in order to comprehend the molecular basis of pS versus pT selectivity. Through this work, we have characterized various factors that encode the binding selectivity for pS and pT. Among them, water molecules, geometrical features and crucial interacting residues were enlisted. This knowledge can shed light on the possible binding partners and help in the design of selective small molecule protein-protein interaction inhibitors for tBRCT domains. Using computational approaches viz. Molecular Dynamics (MD) simulations, GIST analysis and QM/MM, a quantitative comparison of all such factors was made to postulate‘ the minimal determination factors to recognize and bind pS or pT by tBRCT domain containing proteins’.

Keywords: BRCT Domain, Molecular Dynamics, GIST, phosphorylation, QM/MM