Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation
SCIE
SCOPUS
- Title
- Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation
- Authors
- Yunn, NO; Koh, A; Han, S; Lim, JH; Park, S; Lee, J; Kim, E; Jang, SK; Berggren, PO; Ryu, SH
- Date Issued
- 2015-09-18
- Publisher
- Oxford University Press
- Abstract
- Due to their high affinity and specificity, aptamers have been widely used as effective inhibitors in clinical applications. However, the ability to activate protein function through aptamer-protein interaction has not been well-elucidated. To investigate their potential as target-specific agonists, we used SELEX to generate aptamers to the insulin receptor (IR) and identified an agonistic aptamer named IR-A48 that specifically binds to IR, but not to IGF-1 receptor. Despite its capacity to stimulate IR autophosphorylation, similar to insulin, we found that IR-A48 not only binds to an allosteric site distinct from the insulin binding site, but also preferentially induces Y1150 phosphorylation in the IR kinase domain. Moreover, Y1150-biased phosphorylation induced by IR-A48 selectively activates specific signaling pathways downstream of IR. In contrast to insulin-mediated activation of IR, IR-A48 binding has little effect on the MAPK pathway and proliferation of cancer cells. Instead, AKT S473 phosphorylation is highly stimulated by IR-A48, resulting in increased glucose uptake both in vitro and in vivo. Here, we present IR-A48 as a biased agonist able to selectively induce the metabolic activity of IR through allosteric binding. Furthermore, our study also suggests that aptamers can be a promising tool for developing artificial biased agonists to targeted receptors.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/36212
- DOI
- 10.1093/NAR/GKV767
- ISSN
- 0305-1048
- Article Type
- Article
- Citation
- Nucleic Acids Research, vol. 43, no. 16, page. 7688 - 7701, 2015-09-18
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