Title :
O-fucosylation of muscle
agrin determines its ability to cluster acetylcholine
receptors
Abstract :
- Protein O- fucosyltransferase 1 ( Pofut1 ) transfers fucose to serine or threonine on proteins , including Notch receptors , that contain EGF repeats with a particular consensus sequence
- Here we demonstrate that agrin is O-fucosylated in a Pofut1-dependent manner, and that this glycosylation can regulate agrin function
- Fucosylation of recombinant C45 agrin , both active (neural, z8) and inactive (muscle, z0) splice forms, was eliminated when agrin was overexpressed in Pofut1-deficient cells or by mutation of a consensus site for Pofut1 fucosylation ( serine 1726 in the EGF4 domain )
- Loss of O-fucosylation caused a gain of function for muscle agrin such that it stimulated AChR clustering and MuSK phosphorylation in cultured myotubes at levels normally only found with the neural splice form
- Deletion of Pofut1 in cultured primary myotubes and in adult skeletal muscle increased AChR aggregation
- In addition, Pofut1 gene and protein expression and Pofut1 activity of the EGF4 domain of agrin were modulated during neuromuscular development
- These data are consistent with a role for Pofut1 in AChR aggregation during synaptogenesis via the regulation of the synaptogenic activity of muscle agrin