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, Randen L. Patterson

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

One of the major challenges in the genomic era is annotating structure/function to the vast quantities of sequence information now available. Indeed, most of the protein sequence database lacks comprehensive annotation, even when experimental evidence exists. Further, within structurally resolved and functionally annotated protein domains, additional functionalities contained in these domains are not apparent. To add further complication, small changes in the amino-acid sequence can lead to profound changes in both structure and function, underscoring the need for rapid and reliable methods to analyze these types of data. Phylogenetic profiles provide a quantitative method that can relate the structural and functional properties of proteins, as well as their evolutionary relationships. Using all of the structurally resolved Src-Homology-2 (SH2) domains, we demonstrate that knowledge-bases can be used to create single-amino acid phylogenetic profiles which reliably annotate lipid-binding. Indeed, these measures isolate the known phosphotyrosine and hydrophobic pockets as integral to lipid-binding function. In addition, we determined that the SH2 domain of Tec family kinases bind to lipids with varying affinity and specificity. Simulating mutations in Bruton's tyrosine kinase (BTK) that cause X-Linked Agammaglobulinemia (XLA) predict that these mutations alter lipid-binding, which we confirm experimentally. In light of these results, we propose that XLA-causing mutations in the SH3-SH2 domain of BTK alter lipidbinding, which could play a causative role in the XLA-phenotype. Overall, our study suggests that the number of lipid-binding proteins is drastically underestimated and, with further development, phylogenetic profiles can provide a method for rapidly increasing the functional annotation of protein sequences.

Original languageEnglish (US)
Pages (from-to)139-149
Number of pages11
JournalJournal of Proteomics and Bioinformatics
Volume2
Issue number3
DOIs
StatePublished - Mar 1 2009

Fingerprint

Lipids
src Homology Domains
Proteins
Mutation
Amino acids
Molecular Sequence Annotation
Amino Acids
Protein Databases
Phosphotyrosine
Knowledge Bases
Amino Acid Sequence
Carrier Proteins
Phosphotransferases
Phenotype
Bruton type agammaglobulinemia
Agammaglobulinaemia tyrosine kinase

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Computer Science Applications
  • Cell Biology

Cite this

Hong, Yoojin ; Chalkia, Dimitra ; Ko, Kyung Dae ; Bhardwaj, Gaurav ; Chang, Gue Su ; van Rossum, Damian B. ; Patterson, Randen L. / Phylogenetic profiles reveal structural and functional determinants of lipid-binding. In: Journal of Proteomics and Bioinformatics. 2009 ; Vol. 2, No. 3. pp. 139-149.
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Phylogenetic profiles reveal structural and functional determinants of lipid-binding. / Hong, Yoojin; Chalkia, Dimitra; Ko, Kyung Dae; Bhardwaj, Gaurav; Chang, Gue Su; van Rossum, Damian B.; Patterson, Randen L.

In: Journal of Proteomics and Bioinformatics, Vol. 2, No. 3, 01.03.2009, p. 139-149.

Research output: Contribution to journalArticle

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AU - Ko, Kyung Dae

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