title: Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation.
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.
authors.affiliation: The School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Na-Oh
authors.initials: NO
authors.lastname: Yunn
authors.affiliation: The Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Ara
authors.initials: A
authors.lastname: Koh
authors.affiliation: The Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Seungmin
authors.initials: S
authors.lastname: Han
authors.affiliation: The POSTECH Aptamer Initiative Program, POSTECH Biotech Center, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Jong Hun
authors.initials: JH
authors.lastname: Lim
authors.affiliation: The Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Sehoon
authors.initials: S
authors.lastname: Park
authors.affiliation: The Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Jiyoun
authors.initials: J
authors.lastname: Lee
authors.affiliation: The Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Eui
authors.initials: E
authors.lastname: Kim
authors.affiliation: The School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, South Korea The Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea The Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Sung Key
authors.initials: SK
authors.lastname: Jang
authors.affiliation: The Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, South Korea The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.affiliation: The School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, South Korea The Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea The Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, South Korea sungho@postech.ac.kr.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D052157:Aptamers, Nucleotide / Q000378:metabolism / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D052157:Aptamers, Nucleotide; D001786:Blood Glucose; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D005947:Glucose