Structure of macrophage colony stimulating factor bound to FMS: Diverse signaling assemblies of class III receptor tyrosine kinases
Autor: | Xiaolin He, Xiaoyan Chen, Pamela J. Focia, Heli Liu, Ann Hye Ryong Shim |
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Jazyk: | angličtina |
Rok vydání: | 2008 |
Předmět: |
Macrophage colony-stimulating factor
Models Molecular Conformational change Protein Conformation Receptor Macrophage Colony-Stimulating Factor Immunoglobulin domain Calorimetry Receptor tyrosine kinase Humans Tyrosine Receptor reproductive and urinary physiology Multidisciplinary Crystallography biology Macrophage Colony-Stimulating Factor hemic and immune systems Biological Sciences Ligand (biochemistry) biological factors Cell biology Biochemistry embryonic structures biology.protein Signal transduction Signal Transduction |
Popis: | Macrophage colony stimulating factor (M-CSF), through binding to its receptor FMS, a class III receptor tyrosine kinase (RTK), regulates the development and function of mononuclear phagocytes, and plays important roles in innate immunity, cancer and inflammation. We report a 2.4 A crystal structure of M-CSF bound to the first 3 domains (D1–D3) of FMS. The ligand binding mode of FMS is surprisingly different from KIT, another class III RTK, in which the major ligand-binding domain of FMS, D2, uses the CD and EF loops, but not the β-sheet on the opposite side of the Ig domain as in KIT, to bind ligand. Calorimetric data indicate that M-CSF cannot dimerize FMS without receptor-receptor interactions mediated by FMS domains D4 and D5. Consistently, the structure contains only 1 FMS-D1–D3 molecule bound to a M-CSF dimer, due to a weak, hydrophilic M-CSF:FMS interface, and probably a conformational change of the M-CSF dimer in which binding to the second site is rendered unfavorable by FMS binding at the first site. The partial, intermediate complex suggests that FMS may be activated in two steps, with the initial engagement step distinct from the subsequent dimerization/activation step. Hence, the formation of signaling class III RTK complexes can be diverse, engaging various modes of ligand recognition and various mechanistic steps for dimerizing and activating receptors. growth factor signal transduction |
Databáze: | OpenAIRE |
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