Naturally occurring mutations alter the stability of polycystin-1 polycystic kidney disease (PKD) domains

Liang Ma, Meixiang Xu, Julian R. Forman, Jane Clarke, Andres Oberhauser

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Mutations in polycystin-1 (PC1) can cause autosomal dominant polycystic kidney disease, which is a leading cause of renal failure. The available evidence suggests that PC1 acts as a mechanosensor, receiving signals from the primary cilia, neighboring cells, and extracellular matrix. PC1 is a large membrane protein that has a long N-terminal extracellular region (about 3000 amino acids) with a multimodular structure including 16 Ig-like polycystic kidney disease (PKD) domains, which are targeted by many naturally occurring missense mutations. Nothing is known about the effects of these mutations on the biophysical properties of PKD domains. Here we investigate the effects of several naturally occurring mutations on the mechanical stability of the first PKD domain of human PC1 (HuPKDd1). We found that several missense mutations alter the mechanical unfolding pathways of HuPKDd1, resulting in distinct mechanical phenotypes. Moreover, we found that these mutations also alter the thermodynamic stability of a structurally homologous archaeal PKD domain. Based on these findings, we hypothesize that missense mutations may cause autosomal dominant polycystic kidney disease by altering the stability of the PC1 ectodomain, thereby perturbing its ability to sense mechanical signals.

Original languageEnglish (US)
Pages (from-to)32942-32949
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number47
DOIs
StatePublished - Nov 20 2009

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Polycystic Kidney Diseases
Missense Mutation
Mutation
Autosomal Dominant Polycystic Kidney
Cilia
Thermodynamics
Mechanical stability
Renal Insufficiency
Extracellular Matrix
Membrane Proteins
polycystic kidney disease 1 protein
Thermodynamic stability
Phenotype
Amino Acids

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Naturally occurring mutations alter the stability of polycystin-1 polycystic kidney disease (PKD) domains. / Ma, Liang; Xu, Meixiang; Forman, Julian R.; Clarke, Jane; Oberhauser, Andres.

In: Journal of Biological Chemistry, Vol. 284, No. 47, 20.11.2009, p. 32942-32949.

Research output: Contribution to journalArticle

Ma, Liang ; Xu, Meixiang ; Forman, Julian R. ; Clarke, Jane ; Oberhauser, Andres. / Naturally occurring mutations alter the stability of polycystin-1 polycystic kidney disease (PKD) domains. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 47. pp. 32942-32949.
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