Prediction of Protein Binding Regions in Disordered Proteins

Abstract

Many disordered proteins function via binding to a structured partner and undergo a disorder-to-order transition. The coupled folding and binding can confer several functional advantages such as the precise control of binding specificity without increased affinity. Additionally, the inherent flexibility allows the binding site to adopt various conformations and to bind to multiple partners. These features explain the prevalence of such binding elements in signaling and regulatory processes. In this work, we report ANCHOR, a method for the prediction of disordered binding regions. ANCHOR relies on the pairwise energy estimation approach that is the basis of IUPred, a previous general disorder prediction method. In order to predict disordered binding regions, we seek to identify segments that are in disordered regions, cannot form enough favorable intrachain interactions to fold on their own, and are likely to gain stabilizing energy by interacting with a globular protein partner. The performance of ANCHOR was found to be largely independent from the amino acid composition and adopted secondary structure. Longer binding sites generally were predicted to be segmented, in agreement with available experimentally characterized examples. Scanning several hundred proteomes showed that the occurrence of disordered binding sites increased with the complexity of the organisms even compared to disordered regions in general. Furthermore, the length distribution of binding sites was different from disordered protein regions in general and was dominated by shorter segments. These results underline the importance of disordered proteins and protein segments in establishing new binding regions. Due to their specific biophysical properties, disordered binding sites generally carry a robust sequence signal, and this signal is efficiently captured by our method. Through its generality, ANCHOR opens new ways to study the essential functional sites of disordered proteins.

Role of CBS and Bateman Domains in Phosphorylation-Dependent Regulation of a CLC Anion Channel

“…Much of the 14-amino-acid AD is predicted to form a-helix. The ANCHOR method (41,42) predicts that the AD is a protein-protein interaction site, which is consistent with our deletion mutagenesis studies (Table 1; (37)). …”

System-wide Analysis Reveals Intrinsically Disordered Proteins Are Prone to Ubiquitylation after Misfolding Stress

“…A prominent motif enriched corresponded to basophilic serine/threonine kinase sites (see supplemental Table S4 for a complete list). Corroborating these results, we observed the same trend using the independent method ANCHOR to find regions with favorable energetics for protein binding interactions (40) (Fig. 5D, supplemental Fig.…”

Caulobacter PopZ forms an intrinsically disordered hub in organizing bacterial cell poles

“…MoRFs are metastable sequences that often acquire a regular structure on interacting with a binding partner, but they are unable to form strong intrachain interactions on their own (22). They are embedded within larger regions of structural disorder, and they exhibit a high degree of evolutionary conservation in comparison with surrounding sequences (23).…”