2021 Fiscal Year Final Research Report
Molecular mechanism of the pathogenic protein interaction at the C-terminus of amino acid transporter b0,+AT/SLC7A9 in Japanese-type cystinuria
Project/Area Number |
19K07373
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 48040:Medical biochemistry-related
|
Research Institution | Jikei University School of Medicine (2020-2021) Nara Medical University (2019) |
Principal Investigator |
|
Co-Investigator(Kenkyū-buntansha) |
Kongpracha Pornparn 東京慈恵会医科大学, 医学部, ポストドクトラルフェロー (70817767)
|
Project Period (FY) |
2019-04-01 – 2022-03-31
|
Keywords | cystinuria / kidney / amino acid / transporter / structure / biogenesis / calcium / cryo-EM |
Outline of Final Research Achievements |
Amino acid transporter b0,+AT form heterodimer with glycoprotein rBAT to be functional for cystine and dibasic amino acid reabsorption in the kidney. Mutations in either rBAT or b0,+AT cause cystinuria, the renal stone which lead to kidney failure. By state-of-the-art technologies in cryo-electron microscopy and biochemical strategies, we successfully solved the structure of rBAT-b0,+AT. The structure exhibits super-dimer formation of two rBAT-b0,+AT heterodimer. All residues in rBAT-b0,+AT especially the ones responsible for pathogenic mutations were revealed. Getting insight into the transport mechanism of b0,+AT, we have successfully clarified the key residues for the recognition of each type of amino acid substrates. Our finding provides important clues in explaining the molecular pathological mechanisms in cystinuria.
|
Free Research Field |
生物化学、医科学
|
Academic Significance and Societal Importance of the Research Achievements |
rBAT-b0,+ATは、ヘテロ二量体アミノ酸トランスポーター(HAT)の一員として、腎臓でのアミノ酸再吸収に重要な役割を果たし、その欠損がシスチン尿症の原因となることが知られている。本研究の最大の成果は、rBAT-b0,+ATの構造および機能発現機構を明らかにしたことである。この発見により、HATの分子生理学的機構と疾患の病理学的機構との出会いが実現し、これまで長い間説明のつかなかったいくつかのシスチン尿症変異の分子病態を明らかになる。原子レベルでトランスポーターを直接標的とする治療法として、新たなトランスレーショナルリサーチが期待される。
|