Figure 1.

Mutant GlyRS aberrantly binds to the transmembrane receptor neuropilin 1. (A) Schematic of Nrp1 and one of its principal co-receptors, VEGFR2, which together bind to the secreted glycoprotein VEGF-A₁₆₅ (on the left)¹¹. VEGF-A functions in vasculogenesis, angiogenesis, and arteriogenesis, with the latter two processes occurring through Nrp1 and VEGFR2 signalling^{17, 18}. VEGF-A is also critical for nervous system development and maintenance¹⁵. VEGF-A₁₆₅ binding to Nrp1 is mainly dependent by the b1 domain¹². CMT2D-associated mutations in GARS cause a conformational opening of GlyRS, allowing the aberrant binding of mutant GlyRS to the b1 domain of Nrp1 (on the right)¹⁰. This competitively antagonises Nrp1/VEGF-A signalling, which contributes to motor deficits observed in CMT2D mice¹⁰. Schematics are not drawn to scale and adapted from Plein et al.¹⁸ and He et al.¹⁰. (B) Co-immunoprecipitation of endogenous Nrp1 showing aberrant interaction with P234KY, L129P, and C157R GlyRS (ectopically expressed with a V5-tag) in NSC-34 cells. Wild-type GlyRS shows no significant binding to Nrp1. The aberrant interaction is weaker with C157R than with P234KY GlyRS, which correlates with the severity of CMT phenotypes in Gars ^C201R/+ and Gars ^Nmf249/+ mice, respectively.