结构引导诱变揭示多囊蛋白2/多囊蛋白1异构体的离子通道功能。

IF 3.5 4区生物学 Q1 Biochemistry, Genetics and Molecular Biology

FEBS Letters Pub Date : 2025-05-12 DOI:10.1002/1873-3468.70059

Tobias Staudner, Juthamas Khamseekaew, M Gregor Madej, Linda Geiges, Bardha Azemi, Christine Ziegler, Christoph Korbmacher, Alexandr V Ilyaskin

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引用次数: 0

摘要

多囊蛋白-1 （PC1）或多囊蛋白-2 （PC2）突变可导致常染色体显性多囊肾病（ADPKD）。结构数据表明，1个PC1和3个PC2形成异四聚体离子通道，离子渗透途径被PC1 （R4100、R4107和H4111）和PC2 （L677、N681）残基阻断。在这里，我们证明了用丙氨酸取代这些残基导致功能获得（GOF） PC2/PC1结构与PC2同质体相比具有明显的选择性。我们还发现PC2/PC1异构体比PC2同聚体更容易形成。重新解释已发表的PC2/PC1低温电镜数据，结合半胱氨酸修饰实验，表明PC1的成孔结构域采用典型的TRP通道样构象。这种新颖的PC2/PC1 GOF结构为研究ADPKD突变的功能影响提供了机会。

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Ion channel function of polycystin-2/polycystin-1 heteromer revealed by structure-guided mutagenesis.

Mutations in polycystin-1 (PC1) or polycystin-2 (PC2) cause autosomal-dominant polycystic kidney disease (ADPKD). Structural data suggest that one PC1 and three PC2 form heterotetrameric ion channels with an ion permeation pathway blocked by PC1 (R4100, R4107, and H4111) and PC2 (L677, N681) residues. Here, we demonstrate that replacing these residues with alanines results in a gain-of-function (GOF) PC2/PC1 construct with distinct selectivity properties compared to PC2 homomers. We also show preferential formation of PC2/PC1 heteromeric complexes over PC2 homomers. Re-interpretation of published PC2/PC1 cryo-electron microscopy data, combined with cysteine modification experiments, suggests that the pore-forming domain of PC1 adopts a canonical TRP channel-like conformation. This novel PC2/PC1 GOF construct offers the opportunity to investigate the functional impact of ADPKD mutations.

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来源期刊

FEBS Letters 生物-生化与分子生物学

CiteScore

7.00

自引率

2.90%

发文量

303

审稿时长

1.0 months

期刊介绍： FEBS Letters is one of the world''s leading journals in molecular biology and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, Research Letters and Hypotheses that merit urgent publication.