The structure of the Dead ringer-DNA complex reveals how AT-rich interaction domains (ARIDs) recognize DNA.
The AT-rich interaction domain (ARID) is a DNA-binding module found in many eukaryotic transcription factors. Using NMR spectroscopy, we have determined the first ever three-dimensional structure of an ARID--DNA complex (mol. wt 25.7 kDa) formed by Dead ringer from Drosophila melanogaster. ARIDs recognize DNA through a novel mechanism involving major groove immobilization of a large loop that connects the helices of a non-canonical helix-turn-helix motif, and through a concomitant structural rearrangement that produces stabilizing contacts from a beta-hairpin. Dead ringer's preference for AT-rich DNA originates from three positions within the ARID fold that form energetically significant contacts to an adenine-thymine base step. Amino acids that dictate binding specificity are not highly conserved, suggesting that ARIDs will bind to a range of nucleotide sequences. Extended ARIDs, found in several sequence-specific transcription factors, are distinguished by the presence of a C-terminal helix that may increase their intrinsic affinity for DNA. The prevalence of serine amino acids at all specificity determining positions suggests that ARIDs within SWI/SNF-related complexes will interact with DNA non-sequence specifically.
Iwahara
Junji
J
Department of Chemistry and Biochemistry, UCLA-DOE Laboratory of Structural Biology and Molecular Medicine and the Molecular Biology Institute, University of California, Los Angeles, 405 Hilgard Avenue, Los Angeles, CA 90095-1570, USA.
Iwahara
Mizuho
M
Daughdrill
Gary W
GW
Ford
Joseph
J
Clubb
Robert T
RT
D000225:Adenine / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D020029:Base Pairing; D001665:Binding Sites; D016384:Consensus Sequence; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D019077:Helix-Turn-Helix Motifs; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism*; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013936:Thymidine / Q000737:chemistry
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; C098342:Retn protein, Drosophila; D012694:Serine; D004247:DNA; D000225:Adenine; D013936:Thymidine