Sarabipour Sarvenaz, Hristova Kalina
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, United States.
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, United States.
Biochim Biophys Acta. 2016 Jul;1858(7 Pt A):1436-42. doi: 10.1016/j.bbamem.2016.03.027. Epub 2016 Mar 31.
The G380R mutation in the transmembrane domain of FGFR3 is a germline mutation responsible for most cases of Achondroplasia, a common form of human dwarfism. Here we use quantitative Fӧster Resonance Energy Transfer (FRET) and osmotically derived plasma membrane vesicles to study the effect of the achondroplasia mutation on the early stages of FGFR3 signaling in response to the ligands fgf1 and fgf2. Using a methodology that allows us to capture structural changes on the cytoplasmic side of the membrane in response to ligand binding to the extracellular domain of FGFR3, we observe no measurable effects of the G380R mutation on FGFR3 ligand-bound dimer configurations. Instead, the most notable effect of the achondroplasia mutation is increased propensity for FGFR3 dimerization in the absence of ligand. This work reveals new information about the molecular events that underlie the achondroplasia phenotype, and highlights differences in FGFR3 activation due to different single amino-acid pathogenic mutations.
FGFR3跨膜结构域中的G380R突变是一种种系突变，是导致软骨发育不全（一种常见的人类侏儒症形式）的大多数病例的原因。在此，我们使用定量Förster共振能量转移（FRET）和渗透压衍生的质膜囊泡来研究软骨发育不全突变对FGFR3响应配体fgf1和fgf2信号传导早期阶段的影响。通过一种方法，我们能够捕捉到膜细胞质侧响应配体与FGFR3细胞外结构域结合的结构变化，我们观察到G380R突变对FGFR3配体结合二聚体构型没有可测量的影响。相反，软骨发育不全突变最显著的影响是在没有配体的情况下FGFR3二聚化倾向增加。这项工作揭示了有关软骨发育不全表型潜在分子事件的新信息，并突出了由于不同的单氨基酸致病突变导致的FGFR3激活差异。
