ArticleProtein science : a publication of the Protein Society2000
Stability and peptide binding specificity of Btk SH2 domain: molecular basis for X-linked agammaglobulinemia.
Article in Protein science : a publication of the Protein Society, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 41 citations in OpenAlex.
- Two-step mechanism of Bruton's tyrosine kinase membrane recruitment and activation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Mechanism of activation of an ancestral TEC kinase by PIPNpj structural biology · 2026Article
- Clinical relevant Bruton's X-linked tyrosine kinase deficiency in a female with extreme X-chromosome inactivation.Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology · 2025Article
- TACI and BTK gene analysis in predominantly antibody deficiencies among the primary immunodeficiency disorder patients in Bangladesh.Frontiers in medicine · 2025Article
- Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL).Genes · 2023Review
- SH2 Domains: Folding, Binding and Therapeutical Approaches.International journal of molecular sciences · 2022Review
- Use of BTK Inhibitors in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Practical Guidance.Blood and lymphatic cancer : targets and therapy · 2022Review
- Damaging BTK Variant Demonstrated by Carrier, Allele-Specific BTK Expression in B Cells and Monocytes.Journal of clinical immunology · 2019Article
- Achieving a Graded Immune Response: BTK Adopts a Range of Active/Inactive Conformations Dictated by Multiple Interdomain Contacts.Structure (London, England : 1993) · 2017Article
- A novel Bruton's tyrosine kinase gene (BTK) missense mutation in a Chinese family with X-linked agammaglobulinemia.BMC pediatrics · 2014Article
- Article
- A Novel Phosphopeptide Microarray Based Interactome Map in Breast Cancer Cells Reveals Phosphoprotein-GRB2 Cell Signaling Networks.PloS one · 2013Article
- Semi-supervised prediction of SH2-peptide interactions from imbalanced high-throughput data.PloS one · 2013Article
- A novel role for Bruton's tyrosine kinase in hepatocyte growth factor-mediated immunoregulation of dendritic cells.The Journal of biological chemistry · 2011Article
- SH2 domains: modulators of nonreceptor tyrosine kinase activity.Current opinion in structural biology · 2009Review
- SH2-dependent autophosphorylation within the Tec family kinase Itk.Journal of molecular biology · 2009Article
- Genome-wide prediction of SH2 domain targets using structural information and the FoldX algorithm.PLoS computational biology · 2008Article
- Solution structure and phosphopeptide binding of the SH2 domain from the human Bruton's tyrosine kinase.Journal of biomolecular NMR · 2006Article
- Four novel and three recurrent mutations of the BTK gene and pathogenic effects of putative splice mutations.Journal of human genetics · 2006Article
- Role of the BCR complex in B cell development, activation, and leukemic transformation.Immunologic research · 2003Review
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Authors and funding
11 authors at 6 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
X-linked agammaglobulinemia (XLA) is caused by mutations in the Bruton's tyrosine kinase (Btk). The absence of functional Btk leads to failure of B-cell development that incapacitates antibody production in XLA patients leading to recurrent bacterial infections. Btk SH2 domain is essential for phospholipase C-gamma phosphorylation, and mutations in this domain were shown to cause XLA. Recently, the B-cell linker protein (BLNK) was found to interact with the SH2 domain of Btk, and this association is required for the activation of phospholipase C-gamma. However, the molecular basis for the interaction between the Btk SH2 domain and BLNK and the cause of XLA remain unclear. To understand the role of Btk in B-cell development, we have determined the stability and peptide binding affinity of the Btk SH2 domain. Our results indicate that both the structure and stability of Btk SH2 domain closely resemble with other SH2 domains, and it binds with phosphopeptides in the order pYEEI > pYDEP > pYMEM > pYLDL > pYIIP. We expressed the R288Q, R288W, L295P, R307G, R307T, Y334S, Y361C, L369F, and 1370M mutants of the Btk SH2 domain identified from XLA patients and measured their binding affinity with the phosphopeptides. Our studies revealed that mutation of R288 and R307 located in the phosphotyrosine binding site resulted in a more than 200-fold decrease in the peptide binding compared to L295, Y334, Y361, L369, and 1370 mutations in the pY + 3 hydrophobic binding pocket (approximately 3- to 17-folds). Furthermore, mutation of the Tyr residue at the betaD5 position reverses the binding order of Btk SH2 domain to pYIIP > pYLDL > pYDEP > pYMEM > pYEEI. This altered binding behavior of mutant Btk SH2 domain likely leads to XLA.
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