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Conformational Propensities of Peptides Mimicking Transmembrane Helix 5 and Motif C in Wild-type and Mutant Vesicular Acetylcholine Transporters.

Abstract：

:Vesicular acetylcholine transporter (VAChT) is a member of the major facilitator superfamily (MFS). It contains conserved sequence motifs originally defined in the bacterial multidrug resistance transporter family of the MFS. Motif C (GSLV(227) A(228)PPFGGIL) is located at the C-terminal end of transmembrane helix 5 (TM 5) in VAChT. The motif is rich in glycine and proline residues that often have special roles in backbone conformations of TMs. The A228G mutant of VAChT transports > 3-fold faster than wild type does [Chandrasekaran et al. (2006)J. Neurochem. 98, 1551-1559.]. In the current study, the structure of Loop 4/5, TM 5, and Motif C were taken from a three-dimensional homology model for human VAChT. The peptide was immersed in implicit membrane, energy minimized, and molecular dynamics (MD) were simulated. Kinking and wobbling occur in otherwise helical peptide at the hinge residues L226 and V227. MD also were simulated for A228G single-mutant and V227L-A228A double-mutant peptides to investigate the structural roles of the A228G mutation and beta-branching at V227. Mutant peptides exhibit increased wobbling at the hinge residues, but in the double mutant the increase is less. Because Motif C participates in the interface that mediates hypothesized rocker-switch re-orientation of the acetylcholine binding site during transport, dynamics in Motif C might be an important contributor to transport rate.

journal_name

ACS Chem Neurosci

journal_title

ACS chemical neuroscience

authors

Luo J,Parsons SM

doi

10.1021/cn900033s

subject

Has Abstract

pub_date

2010-05-19 00:00:00

pages

381-390

issue

5

issn

1948-7193

journal_volume

1

pub_type

杂志文章

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