Structural Optimization and Interaction Study of a DNA Aptamer to L1 Cell Adhesion Molecule

Abstract

The L1 cell adhesion molecule (L1CAM) plays important roles in the development and plasticity of the nervous system as well as in tumor formation, progression, and metastasis. New ligands are necessary tools for biomedical research and the detection of L1CAM. Here, DNA aptamer yly12 against L1CAM was optimized to have much stronger binding affinity (10–24 fold) at room temperature and 37 °C via sequence mutation and extension. This interaction study revealed that the optimized aptamers (yly20 and yly21) adopted a hairpin structure containing two loops and two stems. The key nucleotides for aptamer binding mainly located in loop I and its adjacent area. Stem I mainly played the role of stabilizing the binding structure. The yly-series aptamers were demonstrated to bind the Ig6 domain of L1CAM. This study reveals a detailed molecular mechanism for the interaction between yly-series aptamers and L1CAM and provides guidance for drug development and detection probe design against L1CAM.

DNA Aptamer Binding Octapeptide Repeat Region of Cellular Prion Protein

“…Thus, a complex target identification step is further needed. In addition, the clear understanding on the molecular structure of aptamer and the binding mechanism between aptamers and their targets is essential for exploiting the biomedical applications of aptamers obtained by cell-SELEX, such as biomarker detection, cellular imaging, and aptamer-based therapy, but it is still a challenge in aptamer research …”

Aptamers: Functional-Structural Studies and Biomedical Applications 2.0

“…The properties and functions of the aptamers can be widely modulated and improved through chemical modifications and sequence variations. For example, the sequence mutation and extension of the yly12 aptamer lead to oligonucleotides showing improved binding affinities towards the sixth immunoglobulin-like domain of the L1CAM (L1 cell adhesion molecule), a protein highly relevant for human tumor formation, progression, and metastasis [3]. Similarly, the sequence of the most studied thrombin binding aptamer, named TBA, that adopts a two-layer G-quadruplex structure, was modified to produce threeand four-layer TBA analogues, which also contain non-natural alpha-deoxyguanosines at specific positions [4].…”