The single-molecule analysis of dynamic regulation of integrin-dependent adhesion processes

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03229
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Kansai Medical University
• Principal Investigator: KINASHI Tatsuo 関西医科大学, 医学部, 教授 (30202039)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 細胞接着 / インテグリン / Rap1 / talin / kindlin3

Outline of Final Research Achievements

Integrins are cell adhesion molecules, which play important roles in cell attachment, migration and accumulation, and also influence cell growth. In this study, we have established single-molecule measurements of integrin binding proteins talin1 and kindlin-3 and thereby revealing the following points: (1) The binding kinetics of talin1 and LFA1 corresponded to that of LFA1 and ICAM1. (2) Kindlin-3 is required for LFA1 to undergo structural changes to an extended/open (high affinity) conformation. (3) When bound to ICAM1, the extended/open conformers activate small GTPase Rap1, which in turn recruits talin1 and kindlin-3 to LFA1 leading to amplification of cell attachment by LFA1. This study has demonstrated the precise adhesion mechanism of LFA1 and would contribute development of therapeutics for immune diseases in which leukocytes adhesion is abnormally accelerated.

Free Research Field

免疫学、分子生物学、細胞生物学

Academic Significance and Societal Importance of the Research Achievements

リンパ球は全身を循環しながら生体防御を行っています。その過程で、LFA1はICAM1という接着分子に結合しますが、その結合の強さを変化させることによって、リンパ球の停止や移動を調節します。この調節過程にはインテグリン結合分子talin1とkindlin-3が関与すると考えられていますが詳細は不明でした。本研究では、一分子計測法という新たな測定方法を用いて、talin1とkindlin-3およびその調節分子であるRap1との連携による作用機序を明らかにしました。この成果はインテグリンの接着を変化させることにつながり、白血球の異常な集積を伴う免疫疾患の新たな治療戦略に役立つと考えられます。