title: Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations.
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.
authors.affiliation: Structural Biology Laboratory, the London Research Institute, Cancer Research UK, London, UK.
authors.forename: Svend
authors.initials: S
authors.lastname: Kjaer
authors.forename: Sarah
authors.initials: S
authors.lastname: Hanrahan
authors.forename: Nick
authors.initials: N
authors.lastname: Totty
authors.forename: Neil Q
authors.initials: NQ
authors.lastname: McDonald
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003545:Cysteine / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism; D056726:Genetic Association Studies; D006627:Hirschsprung Disease / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008322:Mammals; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010802:Phylogeny; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D051096:Proto-Oncogene Proteins c-ret / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D003545:Cysteine
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