Journal of Proteomics & Bioinformatics
Open Access

Abstract

Phylogenetic Profiles Reveal Structural and Functional Determinants of Lipid-binding

Yoojin Hong, Dimitra Chalkia, Kyung Dae Ko, Gaurav Bhardwaj, Gue Su Chang, Damian B. van Rossum and Randen L. Patterson

One of the major challenges in the genomic era is a nnotating structure/function to the vast quantities of se- quence information now available. Indeed, most of t he protein sequence database lacks comprehensive an nota- tion, even when experimental evidence exists. Furth er, within structurally resolved and functionally a nnotated protein domains, additional functionalities contain ed in these domains are not apparent. To add furthe r complica- tion, small changes in the amino-acid sequence can lead to profound changes in both structure and func tion, underscoring the need for rapid and reliable method s to analyze these types of data. Phylogenetic prof iles pro- vide a quantitative method that can relate the stru ctural and functional properties of proteins, as we ll as their evolutionary relationships. Using all of the struct urally resolved Src-Homology-2 (SH2) domains, we de mon- strate that knowledge-bases can be used to create s ingle-amino acid phylogenetic profiles which reliab ly anno- tate lipid-binding. Indeed, these measures isolate the known phosphotyrosine and hydrophobic pockets a s inte- gral to lipid-binding function. In addition, we det ermined that the SH2 domain of Tec family kinases b ind to lipids with varying affinity and specificity. Simulating mutations in Bruton’s tyrosine kinase (BTK) that ca use X-Linked Agammaglobulinemia (XLA) predict that these mutatio ns alter lipid-binding, which we confirm experiment ally. In light of these results, we propose that XLA-caus ing mutations in the SH3-SH2 domain of BTK alter li pid- binding, which could play a causative role in the X LA-phenotype. Overall, our study suggests that the number of lipid-binding proteins is drastically underestimate d and, with further development, phylogenetic profi les can provide a method for rapidly increasing the functio nal annotation of protein sequences.