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Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations

DOI: 10.1038/nsmb.1808 DOI Help

Authors: Svend Kjær (The London Research Institute, Cancer Research UK, U.K.) , Sarah Hanrahan (The London Research Institute, Cancer Research UK, U.K.) , Nick Totty (The London Research Institute, Cancer Research UK, U.K.) , Neil Q Mcdonald (The London Research Institute, Cancer Research UK, U.K.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 17 (6) , PAGES 726 - 731

State: Published (Approved)
Published: May 2010
Diamond Proposal Number(s): 6385

Abstract: The maturation of human RET is adversely affected by a range of missense mutations found in patients with Hirschsprung's disease (HSCR), a complex multigenic disease. Here we show that two N-terminal cadherin-like domains, CLD1 and CLD2 (CLD(1-2)), from human RET adopt a clam-shell arrangement distinct from that of classical cadherins. CLD1 structural elements and disulfide composition are unique to mammals, indicating an unexpected structural diversity within higher and lower vertebrate RET CLD regions. We identify two unpaired cysteines that predispose human RET to maturation impediments in the endoplasmic reticulum and establish a quantitative cell-based RET maturation assay that offers a biochemical correlate of HSCR disease severity. Our findings provide a key conceptual framework and means of testing and predicting genotype-phenotype correlations in HSCR.

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 28/03/2012 12:07

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