Functional selectivity of insulin receptor revealed by aptamer-trapped receptor structures

Junhong Kim, Na-Oh Yunn (), Mangeun Park, Jihan Kim, Seongeun Park, Yoojoong Kim, Jeongeun Noh, Sung Ho Ryu () and Yunje Cho ()
Additional contact information
Junhong Kim: Pohang University of Science and Technology (POSTECH)
Na-Oh Yunn: Pohang University of Science and Technology (POSTECH)
Mangeun Park: Pohang University of Science and Technology (POSTECH)
Jihan Kim: Pohang University of Science and Technology (POSTECH)
Seongeun Park: Pohang University of Science and Technology (POSTECH)
Yoojoong Kim: Pohang University of Science and Technology (POSTECH)
Jeongeun Noh: Pohang University of Science and Technology (POSTECH)
Sung Ho Ryu: Pohang University of Science and Technology (POSTECH)
Yunje Cho: Pohang University of Science and Technology (POSTECH)

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Activation of insulin receptor (IR) initiates a cascade of conformational changes and autophosphorylation events. Herein, we determined three structures of IR trapped by aptamers using cryo-electron microscopy. The A62 agonist aptamer selectively activates metabolic signaling. In the absence of insulin, the two A62 aptamer agonists of IR adopt an insulin-accessible arrowhead conformation by mimicking site-1/site-2’ insulin coordination. Insulin binding at one site triggers conformational changes in one protomer, but this movement is blocked in the other protomer by A62 at the opposite site. A62 binding captures two unique conformations of IR with a similar stalk arrangement, which underlie Tyr1150 mono-phosphorylation (m-pY1150) and selective activation for metabolic signaling. The A43 aptamer, a positive allosteric modulator, binds at the opposite side of the insulin-binding module, and stabilizes the single insulin-bound IR structure that brings two FnIII-3 regions into closer proximity for full activation. Our results suggest that spatial proximity of the two FnIII-3 ends is important for m-pY1150, but multi-phosphorylation of IR requires additional conformational rearrangement of intracellular domains mediated by coordination between extracellular and transmembrane domains.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-34292-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34292-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-34292-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().