Rare Diseases Symptoms Automatic Extraction

Primary and secondary dimer interfaces of the fibroblast growth factor receptor 3 transmembrane domain: characterization via multiscale molecular dynamics simulations.

[achondroplasia]

Receptor tyrosine kinases are single-pass membrane proteins that form dimers within the membrane. The interactions of their transmembrane domains (TMDs) play a key role in dimerization and signaling. Fibroblast growth factor receptor 3 (FGFR3) is of interest as a G380R mutation in its TMD is the underlying cause of ~99% of the cases of achondroplasia, the most common form of human dwarfism. The structural consequences of this mutation remain uncertain: the mutation shifts the position of the TMD relative to the lipid bilayer but does not alter the association free energy. We have combined coarse-grained and all-atom molecular dynamics simulations to study the dimerization of wild-type, heterodimer, and mutant FGFR3 TMDs. The simulations reveal that the helices pack together in the dimer to form a flexible interface. The primary packing mode is mediated by a Gx3G motif. There is also a secondary dimer interface that is more highly populated in heterodimer and mutant configurations that may feature in the molecular mechanism of pathology. Both coarse-grained and atomistic simulations reveal a significant shift of the G380R mutant dimer TMD relative to the bilayer to allow interactions of the arginine side chain with lipid headgroup phosphates.

Diseases presenting "common form" symptom

  • achondroplasia
  • alexander disease
  • benign recurrent intrahepatic cholestasis
  • cadasil
  • child syndrome
  • classical phenylketonuria
  • cutaneous mastocytosis
  • erythropoietic protoporphyria
  • familial mediterranean fever
  • hereditary cerebral hemorrhage with amyloidosis
  • hodgkin lymphoma, classical
  • holt-oram syndrome
  • homocystinuria without methylmalonic aciduria
  • oral submucous fibrosis
  • pendred syndrome
  • primary hyperoxaluria type 1
  • severe combined immunodeficiency
  • thoracic outlet syndrome

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