Structural analysis of CBL protein complexes as a signal suppressor

2014 Fiscal Year Final Research Report

• Project Area: Structural basis of cell-signalling complexes mediating signal perception, transduction and responses
• Project/Area Number: 22121008
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hokkaido University
• Principal Investigator: INAGAKI Fuyuhiko 北海道大学, 先端生命科学研究科(研究院), 特任教授 (70011757)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Keywords: チロシンキナーゼ / 過度的複合体 / 同位体ラベル / NMR / ナノディスク

Outline of Final Research Achievements

CBLis a RING-type E3 ubiquitin ligase that functions as a negative regulator of T-cell activation and growth factor receptor and nonreceptor-type tyrosine kinase signaling. NMR and small angle X-ray scattering analyses revealed that the unphosphorylated N-terminal region of CBL forms a compact structure by an intramolecular interaction, which masks interaction surface of the RING domain with an E2 ubiquitin-conjugating enzyme. Phosphorylation of Y371 disrupts the interdomain interaction to expose the E2 binding surface of the RING domain for efficient ubiquitination.
Ordered phosphorylation is required for receptor tyrosine kinase (RTK) activation; a process mediated by transient dimer formation of the kinase domains. This process is triggered by the tyrosine phosphorylation in the activation-loop. Here, we report structural and biochemical analyses of the tyrosine kinase domain interaction of FGFR required for the initial phosphorylation step.

Free Research Field

構造生物学、NMR