Evidence for an extended hydrogen bond network in the binding site of the nicotinic receptor: role of the vicinal disulfide of the alpha1 subunit

The defining feature of the α subunits of the family of nicotinic acetylcholine receptors is a vicinal disulfide between Cys-192 and Cys-193. Although this structure has played a pivotal role in a number of pioneering studies of nicotinic receptors, its functional role in native receptors remains un...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-09, Vol.286 (37), p.32251
Main Authors: Blum, Angela P, Gleitsman, Kristin Rule, Lester, Henry A, Dougherty, Dennis A
Format: Article
Language:English
Subjects:
Animals
Disulfides - chemistry
Hydrogen Bonding
Peptides - chemistry
Peptides - genetics
Peptides - metabolism
Protein Structure, Secondary
Receptors, Nicotinic - chemistry
Receptors, Nicotinic - genetics
Receptors, Nicotinic - metabolism
Xenopus laevis
Xenopus Proteins
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Summary:The defining feature of the α subunits of the family of nicotinic acetylcholine receptors is a vicinal disulfide between Cys-192 and Cys-193. Although this structure has played a pivotal role in a number of pioneering studies of nicotinic receptors, its functional role in native receptors remains uncertain. Using mutant cycle analysis and unnatural residue mutagenesis, including backbone mutagenesis of the peptide bond of the vicinal disulfide, we have established the presence of a network of hydrogen bonds that extends from that peptide NH, across a β turn to another backbone hydrogen bond, and then across the subunit interface to the side chain of a functionally important Asp residue in the non-α subunit. We propose that the role of the vicinal disulfide is to distort the β turn and thereby properly position a backbone NH for intersubunit hydrogen bonding to the key Asp.
ISSN:1083-351X
DOI:10.1074/jbc.M111.254235