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Science. 2018 Sep 7;361(6406). pii: eaat9819. doi: 10.1126/science.aat9819. Epub 2018 Aug 9.

Structure of the human PKD1-PKD2 complex.

Su Q#1, Hu F#1, Ge X1, Lei J2, Yu S3, Wang T1,4, Zhou Q1, Mei C3, Shi Y5,4.

Author information

1
Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
2
Technology Center for Protein Sciences, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
3
Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
4
Institute of Biology, Westlake Institute for Advanced Study, Westlake University, 18 Shilongshan Road, Xihu District, Hangzhou 310064, Zhejiang Province, China.
5
Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. shi-lab@tsinghua.edu.cn.
#
Contributed equally

Abstract

Mutations in two genes, PKD1 and PKD2, account for most cases of autosomal dominant polycystic kidney disease, one of the most common monogenetic disorders. Here we report the 3.6-angstrom cryo-electron microscopy structure of truncated human PKD1-PKD2 complex assembled in a 1:3 ratio. PKD1 contains a voltage-gated ion channel (VGIC) fold that interacts with PKD2 to form the domain-swapped, yet noncanonical, transient receptor potential (TRP) channel architecture. The S6 helix in PKD1 is broken in the middle, with the extracellular half, S6a, resembling pore helix 1 in a typical TRP channel. Three positively charged, cavity-facing residues on S6b may block cation permeation. In addition to the VGIC, a five-transmembrane helix domain and a cytosolic PLAT domain were resolved in PKD1. The PKD1-PKD2 complex structure establishes a framework for dissecting the function and disease mechanisms of the PKD proteins.

PMID:
30093605
DOI:
10.1126/science.aat9819
[Indexed for MEDLINE]

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