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J Mol Biol. 2005 Jun 17;349(4):861-71.

The remarkable mechanical strength of polycystin-1 supports a direct role in mechanotransduction.

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1
Cambridge University Chemical Laboratory, MRC Centre for Protein Engineering, Lensfield Road, Cambridge CB2 1EW, UK.

Abstract

Polycystin-1 is a large membrane-associated protein that interacts with polycystin-2 in the primary cilia of renal epithelial cells to form a mechanosensitive ion channel. Bending of the cilia induces calcium flow into the cells, mediated by the polycystin complex. Antibodies to polycystin-1 and polycystin-2 abolish this activation. Based on this, it has been suggested that the extracellular region of polycystin-1, which has a number of putative binding domains, may act as a mechanosensor. A large proportion of the extracellular region of polycystin-1 consists of beta-sandwich PKD domains in tandem array. We use atomic force microscopy to investigate the mechanical properties of the PKD domains of polycystin-1. We show that these domains, despite having a low thermodynamic stability, exhibit a remarkable mechanical strength, similar to that of immunoglobulin domains in the giant muscle protein titin. In agreement with the experimental results molecular dynamics simulations performed at low constant force show that the first PKD domain of polycystin (PKDd1) has a similar unfolding time as titin I27, under the same conditions. The simulations suggest that the basis for this mechanical stability is the formation of a force-stabilised intermediate. Our results suggest that these domains will remain folded under external force supporting the hypothesis that polycystin-1 could act as a mechanosensor, detecting changes in fluid flow in the kidney tubule.

PMID:
15894330
DOI:
10.1016/j.jmb.2005.04.008
[Indexed for MEDLINE]
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