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

Svend Kjaer1, Sarah Hanrahan, Nick Totty

  • 1Structural Biology Laboratory, the London Research Institute, Cancer Research UK, London, UK.

Nature Structural & Molecular Biology
|May 18, 2010
PubMed

Insights

Missense mutations in human RET impact maturation, causing Hirschsprung

Area of Science:

  • Molecular biology
  • Genetics
  • Structural biology

Background:

  • Human RET maturation is affected by missense mutations in Hirschsprung's disease (HSCR).
  • HSCR is a complex, multigenic disorder.
  • Understanding RET structure and function is crucial for HSCR research.

Purpose of the Study:

  • To investigate the structural basis of human RET maturation.
  • To identify molecular mechanisms underlying HSCR pathogenesis.
  • To develop a quantitative assay for RET maturation and HSCR genotype-phenotype correlation.

Main Methods:

  • X-ray crystallography to determine the structure of RET cadherin-like domains (CLD(1-2)).
  • Comparative analysis of RET CLD structures across species.
  • Cell-based assays to assess RET maturation and endoplasmic reticulum stress.

Main Results:

  • Human RET CLD(1-2) forms a unique clam-shell structure, differing from classical cadherins.
  • Mammalian RET CLD1 exhibits unique structural elements and disulfide composition.
  • Two unpaired cysteines in RET were identified as key factors causing maturation defects and ER stress.
  • A quantitative cell-based assay was established to correlate RET maturation with HSCR severity.

Conclusions:

  • The unique structure of human RET CLD(1-2) influences its maturation process.
  • Specific cysteine residues are critical for RET maturation and are implicated in HSCR.
  • The developed assay provides a tool for predicting genotype-phenotype correlations in HSCR patients.

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