title: The human TREX2 3' -> 5'-exonuclease structure suggests a mechanism for efficient nonprocessive DNA catalysis.
abstract: The 3' --> 5'-exonucleases process DNA ends in many DNA repair pathways of human cells. Determination of the human TREX2 structure is the first of a dimeric 3'-deoxyribonuclease and indicates how this highly efficient nonprocessive enzyme removes nucleotides at DNA 3' termini. Symmetry in the TREX2 dimer positions the active sites at opposite outer edges providing open access for the DNA. Adjacent to each active site is a flexible region containing three arginines positioned appropriately to bind DNA and to control its entry into the active site. Mutation of these three arginines to alanines reduces the DNA binding capacity by approximately 100-fold with no effect on catalysis. The human TREX2 catalytic residues overlay with the bacterial DnaQ family of 3'-exonucleases confirming the structural conservation of the catalytic sites despite limited sequence identity, and mutations of these residues decrease the still measurable activity by approximately 10(5)-fold, confirming their catalytic role.
authors.affiliation: Department of Biochemistry, Center for Structural Biology, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA.
authors.forename: Fred W
authors.initials: FW
authors.lastname: Perrino
authors.forename: Scott
authors.initials: S
authors.lastname: Harvey
authors.forename: Sara
authors.initials: S
authors.lastname: McMillin
authors.forename: Thomas
authors.initials: T
authors.lastname: Hollis
mesh_terms: D000409:Alanine / Q000737:chemistry; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D004252:DNA Mutational Analysis; D004258:DNA Polymerase III / Q000737:chemistry; D004260:DNA Repair; D019281:Dimerization; D004583:Electrons; D029968:Escherichia coli Proteins / Q000737:chemistry; D005090:Exodeoxyribonucleases / Q000737:chemistry*; D005092:Exonucleases / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D017386:Sequence Homology, Amino Acid
chemical_list: D029968:Escherichia coli Proteins; D010750:Phosphoproteins; D004247:DNA; D001120:Arginine; D004258:DNA Polymerase III; C468316:dnaQ protein, E coli; D005090:Exodeoxyribonucleases; D005092:Exonucleases; C486104:TREX2 protein, human; D000409:Alanine