2007 Fiscal Year Final Research Report Summary
Structzal analysis of receptor-ligand interactions in cell signaling
| Project/Area Number |
16207006
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Structural biochemistry
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| Research Institution | Osaka University |
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Principal Investigator |
TAKAGI Junichi Osaka University, Institute for Protein Research, Professor (90212000)
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| Co-Investigator(Kenkyū-buntansha) |
IWASAKI Kenji Osaka University, Institute for Protein Research, Associate Professor (20342751)
NOGI Terukazu Osaka University, Institute for Protein Research, Assistant Professor (40379102)
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| Project Period (FY) |
2004 – 2007
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| Keywords | sionalino molecules / receptor / ligand / X-ray crystallography / electron microscopy / brain development / reelin / LRP6 |
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| Research Abstract |
A large extracellular glycoprotein reelin directs neuronal migration during the brain development and play fundamental role in the layer formation. It is composed of eight tandem repeats of ~380-residue unit, termed reelin repeat, which has a central EGF module flanked by two homologous subrepeats with no obvious sequence similarity to known proteins. The 1.9A crystal structure of mouse reelin repeat 3 reveals that the subrepeat assumes a β-jelly-roll fold with unexpected structural similarity to carbohydrate binding domains. Despite the intervention by an EGF module, two subdomains make direct contact resulting in a compact overall structure. Electron micrographs of four-domain fragment encompassing 3rd to 6th repeats, which is capable of inducing Dab1 phosphorylation in neuron, show rod-like shape with four blobs. Furthermore, 3D molecular envelope of the fragment obtained by single-particle tomography can be fitted with four concatenated repeat 3 atomic structures, giving the first glimpse of the structural unit for this important class of signaling molecule.
We next found that both receptor binding and subsequent Dab1 phosphorylation occur solely in the segment spanning the fifth and sixth reelin repeats (R5-6). Monomeric fragment exhibited a suboptimal level of signaling activity and artificial oligomerization resulted in a 10-fold increase in activity, indicating the critical importance of higher-order multimerization in physiological reelin. A 2.0A crystal structure from the R5-6 fragment revealed not only a unique domain arrangement wherein two repeats were aligned side by side with the same orientation, but also the unexpected presence of bound Zn ions. Structure-guided alanine mutagenesis of R5-6 revealed that two Lys residues (Lys2360 and Lys2467) constitute a central binding site for the LDLR class A module in the receptor, indicating a strong similarity to the ligand recognition mode shared among the endocytic lipoprotein receptors.
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Research Products
(75 results)
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[Journal Article] Semaphorin 7A initiates T cell-mediated inflammatory responses through al b1 integrin2007
Author(s)
Suzuki, K., Okuno, T., Yamamoto, M., Pasterkamp, R.J., Takegahara, N., Kitao, T., Takagi, J., Rennert, P.D., Kolodkin, A.L., Kumanogoh, A., Kikutani, H
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Journal Title
Nature 446
Pages: 680-684
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The RGD motif in fibronectin is essential for mouse development but dispensable for fibronectin fibril assembly2007
Author(s)
Takahashi, S., Leiss, M., Moser, M., Ohashi, T., Kitao, T., Heckmann, D., Pfeifer, A., Kessler, H., Takagi, T. Erickson, H.P., Fassler, R
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Journal Title
J. Cell Biol 178
Pages: 167-178
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Structure of a receptor-binding reelin fragment and mutational analysis reveal a recognition mechanism similar to endocytic receptors2007
Author(s)
Yasui, N., Nogi, T., Kitao, T., Nakano, Y., Hattori, M.,Takagi J
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Journal Title
Proc. Natl. Acad. Sci. USA 104
Pages: 9988-9993
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] van der Merwe PA, Mardon HJ, and Handford PA alpha Vbeta 6 is a novel receptor for human fibrillin-1 : comparative studies of molecular determinants underlying integrin-RGD affinity and specificity2007
Author(s)
Jovanovic, J, Takagi, J, Choulier, L, Abrescia, NG, Stuart, DI
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Journal Title
J. Biol. Chem 282
Pages: 6743-6751
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Direct interaction of the kringle domain of urokinase-type plasminogen activator(uPA) and integrin alpha v beta 3 induces signal transduction and enhances plasminogen activation.2006
Author(s)
Tarui, T., Akakura, N., Majumdar, M., Andronicos, N., Takagi, J., Mazar, A.P., Bdeir, K., Kuo, A., Yarovoi, S.V., Cines, D.B., Takada, Y
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Journal Title
Thromb Haemost 95
Pages: 524-534
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Ligand-binding specificities of laminin-binding integrins : a comprehensive survey of laminin-integrin interactions using recombinant alpha3betal, a6b1, a7b1 and a6b4 integrins2006
Author(s)
Nishiuchi, R., Takagi, J., Hayashi, M., Ido, H., Yagi, Y., Sanzen, N., Tsuji, T., Yamada, M., Sekiguchi, K
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Journal Title
Matrix Blot 25
Pages: 189-197
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Potentiation of the ligand-binding activity of integrin alpha3 betal via association with tetraspanin CD1512005
Author(s)
Nishiuchi, R., Sanzen, N., Nada, S., Sumida, Y., Wada, Y., Okada, M., Takagi, J., Hasegawa, H., Sekiguchi, K
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Journal Title
Proc Natl Acad Sci USA 102
Pages: 1939-1944
Description
「研究成果報告書概要(欧文)」より
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[Presentation] 電子線トモグラフィー2007
Author(s)
岩崎、憲治
Organizer
第7回日本蛋白質科学会年会
Place of Presentation
仙台国際センター(仙台)
Year and Date
20070524-26
Description
「研究成果報告書概要(和文)」より
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