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Pathogenic Cysteine Removal Mutations in FGFR Extracellular Domains Stabilize Receptor Dimers and Perturb the TM

Sarvenaz Sarabipour1, Kalina Hristova1

  • 1Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21212, USA.

Journal of Molecular Biology
|September 7, 2016
PubMed

Insights

Pathogenic cysteine mutations in fibroblast growth factor receptors (FGFRs) stabilize receptor dimers, altering their structure. This aberrant dimerization and structural changes likely drive disease phenotypes.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • Missense mutations altering cysteine residues in receptor tyrosine kinases (RTKs) are linked to pathologies.
  • These mutations are hypothesized to cause disease by stabilizing active RTK dimers.
  • The stabilizing effect of such mutations on full-length receptors remains unquantified.

Purpose of the Study:

  • To measure the dimer stabilizing effects of pathogenic cysteine substitutions in full-length fibroblast growth factor receptors (FGFRs).
  • To investigate the impact of these mutations on the structural configuration of FGFR transmembrane dimers.

Main Methods:

  • Characterization of dimer stabilities for three full-length FGFR mutants (C178S FGFR1, C342R FGFR2, C228R FGFR3).
  • Analysis of the structural configuration of transmembrane FGFR dimers.

Main Results:

  • The three studied cysteine substitution mutations significantly stabilize FGFR dimers.
  • These mutations were observed to alter the structural configuration of the FGFR transmembrane dimers.

Conclusions:

  • Aberrant dimerization is a likely contributor to pathological phenotypes caused by these FGFR mutations.
  • Perturbed dimer structure resulting from these mutations also likely contributes to disease.
  • Quantifying dimer stability provides insight into the molecular mechanisms of RTK-related pathologies.
Keywords:
FGFRcysteine mutationdimer stabilitydisulfide bondstructural change

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