Molecular basis for recognition of 2',5'-linked oligoadenylates by the N-terminal ankyrin repeat domain of human ribonuclease L.
Ribonuclease L (RNase L) is implicated in both the molecular mechanisms of interferon action and the fundamental control of RNA stability in mammalian cells. RNase L is catalytically active only after binding an unusual activator molecule containing a 5'-phosphorylated 2',5'-linked oligoadenylate, [(pp)p(A2'p5')(n)A] (2-5A), in the N-terminal half. Here we report the crystal structure of the N-terminal ankyrin repeat domain (ANK) of human RNase L complexed with the activator 2-5A. The ANK folds into eight ankyrin repeat elements and forms an extended curved structure with a concave surface. The 2-5A molecule is accommodated in the concavity and interacts with ankyrin repeats 2 to 4. Two structurally equivalent 2-5A binding motifs are found at repeats 2 and 4. The molecular basis for 2-5A recognition by RNase L is essential for designing stable 2-5As with a high likelihood of activating RNase L.
Tanaka
Nobutada
N
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Nakanishi
Masayuki
M
Kusakabe
Yoshio
Y
Goto
Yoshikuni
Y
Kitade
Yukio
Y
Nakamura
Kazuo T
KT
D000227:Adenine Nucleotides / Q000737:chemistry*; D017089:Ankyrin Repeat; D003461:Crystallography; D004722:Endoribonucleases / Q000737:chemistry*; D006801:Humans; D009843:Oligoribonucleotides / Q000737:chemistry*; D017434:Protein Structure, Tertiary
D000227:Adenine Nucleotides; D009843:Oligoribonucleotides; C023505:2',5'-oligoadenylate; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease