SEMINAR

A 3D view of B cell repertoires

Abstract
Emerging technology is enabling the sequencing of individual antibody and T cell receptors on a vast scale, opening up the possibility of observing the dynamics of adaptive immune responses under various conditions. We have extended the view of such data to the molecular level by modeling antibodies in 3D to atomic resolution and then carrying out flexible docking of antigens. Such simulations have several practical uses. First, we can docked models to understand which antigens are driving observed B-cell populations. Second, we can identify candidate therapeutic antibodies, such as broadly neutralizing antibodies against viruses. Third, we can design epitopes to elicit protective antibody or T cell responses. The success of such a structure-based approach depends largely on the accuracy of the underlying simulations. For this reason, we have developed various state-of-the-art modeling tools. These include: MAFFT, a highly efficient and accurate method for multiple sequence alignment MAFFT [1]; OSCAR, an atomic-level force-field for proteins [2]; Kotai Antibody Builder, a server for modeling antibody variable domains [3]; aaRNA and aaDNA, tools for residue-level prediction of nucleotide binding sites on proteins [4].

References

Katoh, K. & Standley, D. M. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Molecular biology and evolution 30, 772-780 (2013).

Liang, S., Zheng, D., Zhang, C. & Standley, D. M. Fast and accurate prediction of protein side-chain conformations. Bioinformatics 27, 2913-2914 (2011).

Yamashita, K. et al. Kotai Antibody Builder: automated high-resolution structural modeling of antibodies. Bioinformatics 30, 3279-3280 (2014).

Li, S., Yamashita, K., Amada, K. M. & Standley, D. M. Quantifying sequence and structural features of protein-RNA interactions. Nucleic acids research 42, 10086-10098 (2014).

BIOGRAPHY

2014-present: Professor, Institute for Virus Research, Kyoto University
2014-present:Visiting Professor, Immunology Frontier Research Center, Osaka University
2008-2014: Associate Professor, Immunology Frontier Research Center, Osaka University
2003-2008: Senior Researcher, Protein Databank, Japan, Osaka Univeristy
1998-2003: Scientific Software Developer, Schrodinger, Inc.
1998: PhD, Department of Chemistry, Columbia University

Research Fields and Interests:
My research focuses mainly on two themes: 3D modeling of immune repertoires and RBP-mediated post-transcriptional regulation. We mine high-throughput sequencing data from B and T cells and use this information in data-driven docking simulations in order to discover new antibodies, antigen or both. We are also working on understanding post-transcriptional regulation at the molecular level by studying novel RNA-protein interactions. Both of these research themes are pursued in close collaboration with experimentalists.

Selected Publications:

Mino, T. et al. Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms. Cell 161, 1058-1073 (2015).
Tartey, S. et al. Akirin2 is critical for inducing inflammatory genes by bridging IkappaB-zeta and the SWI/SNF complex. EMBO J 33, 2332-2348 (2014).
Uehata, T. et al. Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation. Cell 153, 1036-1049 (2013).
Iwasaki, H. et al. The IkappaB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1. Nat Immunol 12, 1167-1175 (2011).
Matsushita, K. et al. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458, 1185-1190 (2009).