Analysis of the REJ module of polycystin-1 using molecular modeling and force-spectroscopy techniques

Meixiang Xu, Liang Ma, Pawel Bujalowski, Feng Qian, R. Bryan Sutton, Andres Oberhauser

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number525231
JournalJournal of Biophysics
DOIs
StatePublished - 2013

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Molecular modeling
Spectrum Analysis
Spectroscopy
Autosomal Dominant Polycystic Kidney
Protein Engineering
Amino Acids
Mutation
Inborn Genetic Diseases
Mechanical stability
Molecular Dynamics Simulation
Renal Insufficiency
Ovum
Amino acids
Proteins
Conformations
Molecular dynamics
Mechanical properties
Molecules
polycystic kidney disease 1 protein
Computer simulation

ASJC Scopus subject areas

  • Biophysics
  • Biomedical Engineering

Cite this

Analysis of the REJ module of polycystin-1 using molecular modeling and force-spectroscopy techniques. / Xu, Meixiang; Ma, Liang; Bujalowski, Pawel; Qian, Feng; Sutton, R. Bryan; Oberhauser, Andres.

In: Journal of Biophysics, 2013.

Research output: Contribution to journalArticle

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AU - Sutton, R. Bryan

AU - Oberhauser, Andres

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