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

J. Biol. Chem., Vol. 282, Issue 14, 10537-10543, April 6, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/14/10537    most recent M700039200v1 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 de Silva, U. Articles by Hollis, T. Search for Related Content PubMed PubMed Citation Articles by de Silva, U. Articles by Hollis, T. Social Bookmarking                      What's this?

The Crystal Structure of TREX1 Explains the 3' Nucleotide Specificity and Reveals a Polyproline II Helix for Protein Partnering^*

From the Department of Biochemistry, Center for Structural Biology, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157

The TREX1 enzyme processes DNA ends as the major 3' 5' exonuclease activity in human cells. Mutations in the TREX1 gene are an underlying cause of the neurological brain disease Aicardi-Goutières syndrome implicating TREX1 dysfunction in an aberrant immune response. TREX1 action during apoptosis likely prevents autoimmune reaction to DNA that would otherwise persist. To understand the impact of TREX1 mutations identified in patients with Aicardi-Goutières syndrome on structure and activity we determined the x-ray crystal structure of the dimeric mouse TREX1 protein in substrate and product complexes containing single-stranded DNA and deoxyadenosine monophosphate, respectively. The structures show the specific interactions between the bound nucleotides and the residues lining the binding pocket of the 3' terminal nucleotide within the enzyme active site that account for specificity, and provide the molecular basis for understanding mutations that lead to disease. Three mutant forms of TREX1 protein identified in patients with Aicardi-Goutières syndrome were prepared and the measured activities show that these specific mutations reduce enzyme activity by 4–35,000-fold. The structure also reveals an 8-amino acid polyproline II helix within the TREX1 enzyme that suggests a mechanism for interactions of this exonuclease with other protein complexes.

Received for publication, January 2, 2007 , and in revised form, February 8, 2007.

The atomic coordinates and structure factors (code 2OA8 and 2IOC) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Grant RO1 GM069962 (to F. W. P.) and American Cancer Society Grant RSG-04-187-01-GMC (to T. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Medical Center Blvd., Winston-Salem, NC 27157. Tel.: 336-716-0768; Fax: 336-777-3242; E-mail: thollis{at}wfubmc.edu.

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

This article has been cited by other articles:

				F. W. Perrino, U. de Silva, S. Harvey, E. E. Pryor Jr., D. W. Cole, and T. Hollis Cooperative DNA Binding and Communication across the Dimer Interface in the TREX2 3' -> 5'-Exonuclease J. Biol. Chem., August 1, 2008; 283(31): 21441 - 21452. [Abstract] [Full Text] [PDF]