Congenital myasthenia–related AChR δ subunit mutation interferes with intersubunit communication essential for channel gating
Xin-Ming Shen, … , Steven M. Sine, Andrew G. Engel
Xin-Ming Shen, … , Steven M. Sine, Andrew G. Engel
Published April 8, 2008
Citation Information: J Clin Invest. 2008;118(5):1867-1876. https://doi.org/10.1172/JCI34527.
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Research Article Muscle biology

Congenital myasthenia–related AChR δ subunit mutation interferes with intersubunit communication essential for channel gating

Abstract

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 δ 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 δL42, or substitutions of Pro along the local protein chain, also slowed channel opening. Substitution of Pro for Leu in the ε subunit slowed opening, whereas this substitution had no effect in the β subunit and actually sped opening in the α subunit. Analyses of energetic coupling between residues at the subunit interface showed that δL42 is functionally linked to αT127, a key residue in the adjacent α subunit required for rapid channel opening. Thus, δL42 is part of an intersubunit network that enables ACh binding to rapidly open the AChR channel, which may be compromised in patients with CM.

Authors

Xin-Ming Shen, Taku Fukuda, Kinji Ohno, Steven M. Sine, Andrew G. Engel

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Figure 1

Structural model of extracellular and transmembrane domains of the AChR α and δ subunits (Protein Data Bank code 2BG9).

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Structural model of extracellular and transmembrane domains of the AChR ...
αW149 is at the center of the ligand binding site. In the transition zone, the indicated N41 and L42 residues are in the β1 strand of the δ subunit. δN41 is near Y127 in the α subunit.