Shen_2008_J.Clin.Invest_118_1867

Congenital myasthenias (CMs) arise from defects in neuromuscular junction-associated proteins. Deciphering the molecular bases of the CMs is required for therapy and illuminates structure-function relationships in these proteins. Here, we analyze the effects of a mutation in 1 of 4 homologous subunits in the AChR from a CM patient, a Leu to Pro mutation at position 42 of the delta subunit. The mutation is located in a region of contact between subunits required for rapid opening of the AChR channel and impedes the rate of channel opening. Substitutions of Gly, Lys, or Asp for deltaL42, or substitutions of Pro along the local protein chain, also slowed channel opening. Substitution of Pro for Leu in the epsilon subunit slowed opening, whereas this substitution had no effect in the beta subunit and actually sped opening in the alpha subunit. Analyses of energetic coupling between residues at the subunit interface showed that deltaL42 is functionally linked to alphaT127, a key residue in the adjacent alpha subunit required for rapid channel opening. Thus, deltaL42 is part of an intersubunit network that enables ACh binding to rapidly open the AChR channel, which may be compromised in patients with CM.