HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 26, 18184-18192, June 30, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/26/18184    most recent M600349200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, Y. Articles by Chang, Y. Search for Related Content PubMed PubMed Citation Articles by Chen, Y. Articles by Chang, Y. Social Bookmarking                      What's this?

Evolutionarily Conserved Allosteric Network in the Cys Loop Family of Ligand-gated Ion Channels Revealed by Statistical Covariance Analyses^*

Yonghui Chen, Kevin Reilly, and Yongchang Chang¹

From the Department of Computer and Information Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294 and the Division of Neurobiology, Barrow Neurological Institute, Phoenix, Arizona 85013

The Cys loop family of ligand-gated ion channels mediate fast synaptic transmission for communication between neurons. They are allosteric proteins, in which binding of a neurotransmitter to its binding site in the extracellular amino-terminal domain triggers structural changes in distant transmembrane domains to open a channel for ion flow. Although the locations of binding site and channel gating machinery are well defined, the structural basis of the activation pathway coupling binding and channel opening remains to be determined. In this paper, by analyzing amino acid covariance in a multiple sequence alignment, we have identified an energetically interconnected network in the Cys loop family of ligand-gated ion channels. Statistical coupling and correlated mutational analyses along with clustering revealed a highly coupled cluster. Mapping the positions in the cluster onto a three-dimensional structural model demonstrated that these highly coupled positions form an interconnected network linking experimentally identified binding domains through the coupling region to the gating machinery. In addition, these highly coupled positions are also condensed in the transmembrane domains, which are a recent focus for the sites of action of many allosteric modulators. Thus, our results revealed a genetically interconnected network that potentially plays an important role in the allosteric activation and modulation of the Cys loop family of ligand-gated ion channels.

Received for publication, January 12, 2006 , and in revised form, March 20, 2006.

^* This work was supported by funds from the Barrow Neurological Foundation and Women's Board (to Y. Chang). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Neurobiology, Barrow Neurological Institute, 350 West Thomas Rd., Phoenix, AZ 85013. Tel.: 602-406-6192; Fax: 602-406-4172; E-mail: yongchang.chang{at}chw.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Zhang, F. Xue, and Y. Chang Agonist- and antagonist-induced conformational changes of loop F and their contributions to the {rho}1 GABA receptor function J. Physiol., January 1, 2009; 587(1): 139 - 153. [Abstract] [Full Text] [PDF]

				Y. Liu, E. Eyal, and I. Bahar Analysis of correlated mutations in HIV-1 protease using spectral clustering Bioinformatics, May 15, 2008; 24(10): 1243 - 1250. [Abstract] [Full Text] [PDF]