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

J. Biol. Chem., Vol. 282, Issue 44, 32256-32263, November 2, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/44/32256    most recent M706231200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brock, M. Articles by Cheng, X. Search for Related Content PubMed PubMed Citation Articles by Brock, M. Articles by Cheng, X. Social Bookmarking                      What's this?

Conformational Analysis of Epac Activation Using Amide Hydrogen/Deuterium Exchange Mass Spectrometry^*

Melissa Brock¹, Fenghui Fan¹, Fang C. Mei, Sheng Li, Christopher Gessner, Virgil L. Woods, Jr., Supported by NCI, National Institutes of Health, Public Health Service Grants CA099835, CA118595, GM037684, AI0220221, and AI022160 and Discovery Grant (UC10591) from the University of California Industry–University Cooperative Research Program², and Xiaodong Cheng, Supported by NIGMS, National Institutes of Health, Public Health Service Grant GM066170 and American Heart Association Grant-in-Aid 0755049Y³

From the Department of Pharmacology and Toxicology and Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas 77555-1031 and the Department of Medicine and Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California 92093-0656

Exchange proteins directly activated by cAMP (Epac) play important roles in mediating the effects of cAMP through the activation of downstream small GTPases, Rap. To delineate the mechanism of Epac activation, we probed the conformation and structural dynamics of Epac using amide hydrogen/deuterium exchange and structural modeling. Our studies show that cAMP induces significant conformational changes that lead to a spatial rearrangement of the regulatory components of Epac and allows the exposure of the catalytic core for effector binding without imposing significant conformational change on the catalytic core. Homology modeling and comparative structural analyses of the cAMP binding domains of Epac and cAMP-dependent protein kinase (PKA) lead to a model of Epac activation, in which Epac and PKA activation by cAMP employs the same underlying principle, although the detailed structural and conformational changes associated with Epac and PKA activation are significantly different.

Received for publication, July 30, 2007 , and in revised form, September 4, 2007.

^* 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 Both contributed equally to this work.

² To whom correspondence may be addressed: Dept. of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla CA 92093-0656. Tel.: 858-534-2180; Fax: 858-534-2606; E-mail: vwoods{at}ucsd.edu. ³ To whom correspondence may be addressed: Dept. of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1031. Tel.: 409-772-9656; Fax: 409-772-9642; E-mail: xcheng{at}utmb.edu.

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

This article has been cited by other articles:

				R. Das, M. T. Mazhab-Jafari, S. Chowdhury, S. SilDas, R. Selvaratnam, and G. Melacini Entropy-driven cAMP-dependent Allosteric Control of Inhibitory Interactions in Exchange Proteins Directly Activated by cAMP J. Biol. Chem., July 11, 2008; 283(28): 19691 - 19703. [Abstract] [Full Text] [PDF]

				S. M. Harper, H. Wienk, R. W. Wechselberger, J. L. Bos, R. Boelens, and H. Rehmann Structural Dynamics in the Activation of Epac J. Biol. Chem., March 7, 2008; 283(10): 6501 - 6508. [Abstract] [Full Text] [PDF]