| Project/Area Number |
19K07373
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 48040:Medical biochemistry-related
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| Research Institution | Jikei University School of Medicine (2020-2021)
Nara Medical University (2019) |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
Kongpracha Pornparn (コンプラシャ ポーンパン) 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)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | cystinuria / kidney / amino acid / transporter / structure / biogenesis / calcium / cryo-EM / cystine / Transporter / Cystinuria / Structure / Amino acids / SLC7 / Kidney disease / Cystine / Mutation |
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| Outline of Research at the Start |
Cystinuria, a kidney disease characterized by cystine stones, is caused by mutations in cystine transporter b0,+AT or rBAT. Japanese-type cystinuria is caused by P482L, a C-terminal mutation of b0,+AT. We aim to examine the pathogenic mechanism of P482L, which will enlighten a pathogenic feature of transporters and be applied for translational research.
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| 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.
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| 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。
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