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

Kjaer, S; Hanrahan, S; Totty, N; McDonald, NQ; (2010) Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations. Nat Struct Mol Biol , 17 726 - 731. 10.1038/nsmb.1808.

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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.

Type:Article
Title:Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations
DOI:10.1038/nsmb.1808
Additional information: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.
Keywords:Amino Acid Sequence Animals Cysteine Endoplasmic Reticulum Genetic Association Studies Hirschsprung Disease Humans Mammals Models, Molecular Molecular Sequence Data Mutation, Missense Phylogeny Protein Folding Protein Interaction Domains and Motifs Protein Multimerization Protein Processing, Post-Translational Proto-Oncogene Proteins c-ret Sequence Homology, Amino Acid Static Electricity
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Life Sciences

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