Structural model of the TRPP2/PKD1 C-terminal coiled-coil complex produced by a combined computational and experimental approach

Year
2011
Type(s)
Authors
Zhu, Jiang Yu, Y. Ulbrich, M. H. Li, M. H. Isacoff, E. Y. Honig, B. Yang, J.
Source
Proceedings of the National Academy of Sciences of the United States of America 2011 108:10133-10138
Url
http://dx.doi.org/10.1073/pnas.1017669108

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in TRPP2 and PKD1, which form an ion channel/receptor complex containing three TRPP2 and one PKD1. A TRPP2 C-terminal coiled-coil trimer, critical for the assembly of this complex, associates with a single PKD1 C-terminal coiled-coil. Many ADPKD pathogenic mutations result in the abolishment of the TRPP2/PKD1 coiled-coil complex. To gain molecular and functional insights into this heterotetrameric complex, we computationally constructed a structural model by using a two-step docking strategy, based on a known crystal structure of the TRPP2 coiled-coil trimer. The model shows that this tetrameric complex has a novel di-trimer configuration: An upstream trimer made of three TRPP2 helices and a downstream trimer made of two TRPP2 helices and one PKD1 helix. Mutagenesis and biochemical analysis identified critical TRPP2/PKD1 interface contacts essential for the heteromeric coiled-coil complex. Mutation of these interface positions in the full-length proteins showed that these interactions were critical for the assembly of the full-length complex in cells. Our results provide a means to specifically weaken the TRPP2 and PKD1 association, thus facilitating future in vitro and in vivo studies on the functional importance of this association.

 

Technology Platform

Protein Structure Prediction

Research Topics

Molecular Complexes