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Structural and molecular basis of the assembly of the TRPP2/PKD1 complex

Yu, Y., Ulbrich, M., Li, M.H., Buraei, Z., Chen, X.Z., Ong, A.C.M., Tong, L., Isacoff, E.Y. and Yang, J. (2009) Structural and molecular basis of the assembly of the TRPP2/PKD1 complex. Proceedings of the National Academy of Sciences of the United States of America, 106 (28). pp. 11558-11563. ISSN 0027-8424

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Abstract

Mutations in PKD1 and TRPP2 account for nearly all cases of autosomal dominant polycystic kidney disease (ADPKD). These 2 proteins form a receptor/ion channel complex on the cell surface. Using a combination of biochemistry, crystallography, and a single-molecule method to determine the subunit composition of proteins in the plasma membrane of live cells, we find that this complex contains 3 TRPP2 and 1 PKD1. A newly identified coiled-coil domain in the C terminus of TRPP2 is critical for the formation of this complex. This coiled-coil domain forms a homotrimer, in both solution and crystal structure, and binds to a single coiled-coil domain in the C terminus of PKD1. Mutations that disrupt the TRPP2 coiled-coil domain trimer abolish the assembly of both the full-length TRPP2 trimer and the TRPP2/PKD1 complex and diminish the surface expression of both proteins. These results have significant implications for the assembly, regulation, and function of the TRPP2/PKD1 complex and the pathogenic mechanism of some ADPKD-producing mutations.

Item Type: Article
Copyright, Publisher and Additional Information: © 2009 National Academy of Sciences. This is an author produced version of a paper subsequently published in Proceedings of the National Academy of Sciences of the United States of America. Uploaded in accordance with the publisher's self-archiving policy.
Keywords: autosomal dominant polycystic kidney disease; single-molecule imaging; stoichiometry; transient receptor potential channel; X-ray crystallography
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield) > Clinical Sciences Division North (Sheffield) > Sheffield Kidney Institute
Depositing User: Miss Anthea Tucker
Date Deposited: 05 Aug 2009 09:54
Last Modified: 08 Feb 2013 16:58
Published Version: http://dx.doi.org/10.1073/pnas.0903684106
Status: Published
Publisher: National Academy of Sciences
Refereed: Yes
Identification Number: 10.1073/pnas.0903684106
URI: http://eprints.whiterose.ac.uk/id/eprint/9053

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