The Solution Structure and Internal Motions of a Fragment of the Cytidine-rich Strand of the Human Telomere

ISSN： 0022-2836

Source： Journal of Molecular Biology, Vol.299, Iss.1, 2000-05, pp. : 123-144

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Abstract

We present the solution structure of d(CCCTA₂CCCTA₂CCCTA₂CCCT), a fragment of the vertebrate telomere which folds intramolecularly. The four cytidine stretches form an i-motif which includes six intercalated C·C⁺ pairs and terminates with the cytidines at the 5′ extremity of each stretch. Above, the second TA₂ linker loops across one of the narrow grooves, while at the bottom, the first and third linkers loop across the wide grooves.At 30 °C, the spectra of the first and third linkers are quasi-degenerate. Severe broadening at lower temperature indicates that this results from motional averaging between at least two structures of each bottom loop, and makes it impossible to solve the configuration of the bottom loops directly, in contrast to the rest of the structure.We therefore turned to the modified sequence d(CCCTA₂ 5mCCCTA₂CCCUA₂CCCT) in which the two base substitutions (underlined) break the quasi-symmetry between linkers 1 and 3. The three loops follow approximately the hairpin “second pattern” of Hilbers. In the first loop, T4 is in the syn orientation, whereas its analog in the third loop, U16, oriented anti, is in a central location, where it interacts with bases of both loops, thus contributing to their tight association. The only motion is a syn/anti flip of A18 in the third loop.Returning to the telomere fragment, we show that each of the bottom loops switches between the structures identified in the first and third loops of the modified structure. The motions are concerted, and the resulting configurations of the bottom loop cluster present a bulge to either right (T4 syn) or left (T16 syn).