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Revealing structural peculiarities of homopurine GA repetition stuck by i-motif clip

ABSTRACT: Abstract Non-canonical forms of nucleic acids represent challenging objects for both structure-determination and investigation of their potential role in living systems. In this work, we uncover a structure adopted by GA repetition locked in a parallel homoduplex by an i-motif. A series of DNA oligonucleotides comprising GAGA segment and C3 clip is analyzed by NMR and CD spectroscopies to understand the sequence–structure–stability relationships. We demonstrate how the relative position of the homopurine GAGA segment and the C3 clip as well as single-base mutations (guanine deamination and cytosine methylation) affect base pairing arrangement of purines, i-motif topology and overall stability. We focus on oligonucleotides C3GAGA and methylated GAGAC3 exhibiting the highest stability and structural uniformity which allowed determination of high-resolution structures further analyzed by unbiased molecular dynamics simulation. We describe sequence-specific supramolecular interactions on the junction between homoduplex and i-motif blocks that contribute to the overall stability of the structures. The results show that the distinct structural motifs can not only coexist in the tight neighborhood within the same molecule but even mutually support their formation. Our findings are expected to have general validity and could serve as guides in future structure and stability investigations of nucleic acids.

SUBMITTER: Novotny A

PROVIDER: S-EPMC8599794 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:?-Crystallin is the major protein of the eye lens and a member of the family of small heat-shock proteins. Its concentration in the human eye lens is extremely high (about 450 mg/mL). Three-dimensional structure of native ?-crystallin is unknown. First of all, this is the result of the highly heterogeneous nature of ?-crystallin, which hampers obtaining it in a crystalline form. The modeling based on the electron microscopy (EM) analysis of ?-crystallin preparations shows that the main population of the ?-crystallin polydisperse complex is represented by oligomeric particles of rounded, slightly ellipsoidal shape with the diameter of about 13.5 nm. These complexes have molecular mass of about 700 kDa. In our opinion, the heterogeneity of the ?-crystallin complex makes it impossible to obtain a reliable 3D model. In the literature, there is evidence of an enhanced chaperone function of ?-crystallin during its dissociation into smaller components. This may indirectly indicate that the formation of heterogeneous complexes is probably necessary to preserve ?-crystallin in a state inactive before stressful conditions. Then, not only the heterogeneity of the ?-crystallin complex is an evolutionary adaptation that protects ?-crystallin from crystallization but also the enhancement of the function of ?-crystallin during its dissociation is also an evolutionary acquisition. An analysis of the literature on the study of ?-crystallin in vitro led us to the assumption that, of the two ?-crystallin isoforms (?A- and ?B-crystallins), it is ?A-crystallin that plays the role of a special chaperone for ?B-crystallin. In addition, our data on X-ray diffraction analysis of ?-crystallin at the sample concentration of about 170-190 mg/mL allowed us to assume that, at a high concentration, the eye lens ?-crystallin can be in a gel-like stage. Finally, we conclude that, since all the accumulated data on structural-functional studies of ?-crystallin were carried out under conditions far from native, they cannot adequately reflect the features of the functioning of ?-crystallin in vivo.

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Revealing structural peculiarities of homopurine GA repetition stuck by i-motif clip

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