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

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

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1867-1876
Number of pages10
JournalJournal of Clinical Investigation
Volume118
Issue number5
DOIs
StatePublished - May 1 2008

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Congenital Myasthenic Syndromes
Communication
Mutation
Proteins
Neuromuscular Junction
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

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Congenital myasthenia-related AChR δ subunit mutation interferes with intersubunit communication essential for channel gating. / Shen, Xin Ming; Fukuda, Taku; Ohno, Kinji; Sine, Steven M; Engel, Andrew G.

In: Journal of Clinical Investigation, Vol. 118, No. 5, 01.05.2008, p. 1867-1876.

Research output: Contribution to journalArticle

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AU - Ohno, Kinji

AU - Sine, Steven M

AU - Engel, Andrew G

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N2 - 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.

AB - 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.

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