%0 Journal Article
%T Mechanism of PhosphoThreonine/Serine Recognition and Specificity for Modular Domains from All-atom Molecular Dynamics
%A Yu-ming M Huang
%A Chia-en A Chang
%J BMC Biophysics
%D 2011
%I BioMed Central
%R 10.1186/2046-1682-4-12
%X Simulations carried out included wide-type and mutated systems. Through analysis of MD simulations, we found that the conserved His residue defines dual loops feature of the FHA domain, which creates a small cavity reserved for only the methyl group of pThr. These well-organized loop interactions directly response to the pThr binding selectivity, while single loop (the 2nd phosphobinding site of FHA) or in combination with ¦Á-helix (BRCT repeats) or ¦Â-sheet (WW domain) fail to differentiate pThr/pSer.Understanding the domain pre-organizations constructed by conserved residues and the driving force of domain-phosphopeptide recognition provides structural insight into pThr specific binding, which also helps in engineering proteins and designing peptide inhibitors.Protein phosphorylation is widely exploited in DNA damage repair, signal transduction, cell growth and cell cycle regulation; the cascades of downstream signals can be triggered by grabbing a certain phosphoprotein [1-6]. Elucidating the characteristics of phosphopeptide recognition is fundamental to study cellular functions [7]. The phosphoproteins are usually classified into two families, phosphotyrosine (pTyr)-containing and phosphoserine (pSer)/phosphothreonine (pThr)-containing sequences which are phosphorylated and dephosphorylated by different categories of kinases (e.g., pThr/pSer kinase and pThr kinase) and phosphatases [8]. Recent studies discovered a few modular domains that particularly recognize pThr/pSer- or pThr-containing sequences, such as the breast-cancer-associated protein BRCA1 C-terminal (BRCT) repeats, WW domain and forkhead-associated (FHA) domain [9]. Among them, the FHA domain differentiates pThr-containing peptides from pSer-containing peptides, although the difference is only one methyl group [10-15]. Because Ser/Thr kinase phosphorylates both residues, the FHA domain can efficiently reduce potential interaction sites by specifically binding to pThr-containing regions. Although expe
%U http://www.biomedcentral.com/2046-1682/4/12