Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations
| Autor: | Neil Q. McDonald, Sarah Hanrahan, Nick Totty, Svend Kjaer |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Protein Folding congenital hereditary and neonatal diseases and abnormalities endocrine system diseases Molecular Sequence Data Static Electricity Cell Mutation Missense Structural diversity Disease Biology Endoplasmic Reticulum Disease severity Structural Biology medicine Animals Humans Missense mutation Protein Interaction Domains and Motifs In patient Amino Acid Sequence Cysteine Hirschsprung Disease Molecular Biology Genetic Association Studies Phylogeny Mammals Genetics Sequence Homology Amino Acid Cadherin Endoplasmic reticulum Proto-Oncogene Proteins c-ret medicine.anatomical_structure Protein Multimerization Protein Processing Post-Translational |
| Zdroj: | Nature Structural & Molecular Biology. 17:726-731 |
| ISSN: | 1545-9985 1545-9993 |
| DOI: | 10.1038/nsmb.1808 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|