Analysis of the REJ Module of Polycystin-1 Using Molecular Modeling and Force-Spectroscopy Techniques

Polycystin-1 is a large transmembrane protein, which, when mutated, causes autosomal dominant polycystic kidney disease, one of the most common life-threatening genetic diseases that is a leading cause of kidney failure. The REJ (receptor for egg lelly) module is a major component of PC1 ectodomain...

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Veröffentlicht in:Journal of Biophysics 2013, Vol.2013 (2013), p.17-27
Hauptverfasser: Xu, Meixiang, Ma, Liang, Bujalowski, Paul J., Qian, Feng, Sutton, R. Bryan, Oberhauser, Andres F.
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Sprache:eng
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Zusammenfassung:Polycystin-1 is a large transmembrane protein, which, when mutated, causes autosomal dominant polycystic kidney disease, one of the most common life-threatening genetic diseases that is a leading cause of kidney failure. The REJ (receptor for egg lelly) module is a major component of PC1 ectodomain that extends to about 1000 amino acids. Many missense disease-causing mutations map to this module; however, very little is known about the structure or function of this region. We used a combination of homology molecular modeling, protein engineering, steered molecular dynamics (SMD) simulations, and single-molecule force spectroscopy (SMFS) to analyze the conformation and mechanical stability of the first ~420 amino acids of REJ. Homology molecular modeling analysis revealed that this region may contain structural elements that have an FNIII-like structure, which we named REJd1, REJd2, REJd3, and REJd4. We found that REJd1 has a higher mechanical stability than REJd2 (~190 pN and 60 pN, resp.). Our data suggest that the putative domains REJd3 and REJd4 likely do not form mechanically stable folds. Our experimental approach opens a new way to systematically study the effects of disease-causing mutations on the structure and mechanical properties of the REJ module of PC1.
ISSN:1687-8000
1687-8019
DOI:10.1155/2013/525231