β2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding
| العنوان: | β2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding |
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| المؤلفون: | Jari Ylänne, Heikki Takala, Carl G. Gahmberg, Susanna C. Fagerholm, Maarit Takatalo, Maria Aatonen, Elisa M. Nurminen, Tiila R. Kiema, Tomas Strandin, Susanna M. Nurmi |
| المصدر: | Blood. 112:1853-1862 |
| بيانات النشر: | American Society of Hematology, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Models, Molecular, Talin, Threonine, animal structures, Filamins, T-Lymphocytes, Static Electricity, Immunology, Integrin, CD18, macromolecular substances, Plasma protein binding, In Vitro Techniques, Filamin, Biochemistry, Jurkat Cells, 03 medical and health sciences, Filamin binding, Contractile Proteins, 0302 clinical medicine, Cell Adhesion, Humans, Protein Interaction Domains and Motifs, Phosphorylation, Cell adhesion, 030304 developmental biology, 0303 health sciences, Binding Sites, biology, Chemistry, Microfilament Proteins, Cell Biology, Hematology, Intercellular Adhesion Molecule-1, Talin binding, Recombinant Proteins, Cell biology, 14-3-3 Proteins, Amino Acid Substitution, CD18 Antigens, Multiprotein Complexes, 030220 oncology & carcinogenesis, biology.protein, Protein Binding |
| الوصف: | Leukocyte integrins of the β2 family are essential for immune cell-cell adhesion. In activated cells, β2 integrins are phosphorylated on the cytoplasmic Thr758, leading to 14-3-3 protein recruitment to the β2 integrin. The mutation of this phosphorylation site impairs cell adhesion, actin reorganization, and cell spreading. Thr758 is contained in a Thr triplet of β2 that also mediates binding to filamin. Here, we investigated the binding of filamin, talin, and 14-3-3 proteins to phosphorylated and unphosphorylated β2 integrins by biochemical methods and x-ray crystallography. 14-3-3 proteins bound only to the phosphorylated integrin cytoplasmic peptide, with a high affinity (Kd, 261 nM), whereas filamin bound only the unphosphorylated integrin cytoplasmic peptide (Kd, 0.5 mM). Phosphorylation did not regulate talin binding to β2 directly, but 14-3-3 was able to outcompete talin for the binding to phosphorylated β2 integrin. X-ray crystallographic data clearly explained how phosphorylation eliminated filamin binding and induced 14-3-3 protein binding. Filamin knockdown in T cells led to an increase in stimulated cell adhesion to ICAM-1–coated surfaces. Our results suggest that the phosphorylation of β2 integrins on Thr758 acts as a molecular switch to inhibit filamin binding and allow 14-3-3 protein binding to the integrin cytoplasmic domain, thereby modulating T-cell adhesion. |
| تدمد: | 1528-0020 0006-4971 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ca34bb23200e71f7bd479de107520e12 https://doi.org/10.1182/blood-2007-12-127795 |
| رقم الأكسشن: | edsair.doi.dedup.....ca34bb23200e71f7bd479de107520e12 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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