Insulin receptor-inspired soluble insulin binder

Christopher Mendoza; Cameron Hanegan; Alek Sperry; Logan Vargas; Trevor Case; Benjamin Bikman; Dario Mizrachi

doi:10.1016/j.ejcb.2023.151293

Insulin receptor-inspired soluble insulin binder

Christopher Mendoza, Cameron Hanegan, Alek Sperry, Logan Vargas, Trevor Case, Benjamin Bikman, Dario Mizrachi

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

The insulin receptor (IR) is a 320 kDa membrane receptor tyrosine kinase mediating the pleiotropic actions of insulin, leading to phosphorylation of several intracellular substrates including serine/threonine-protein kinase (AKT1), and IR autophosphorylation. Structural details of the IR have been recently revealed. A high-binding insulin site, L1 (K_d =2 nM), consists of two distant domains in the primary sequence of the IR. Our design simplified the L1 binding site and transformed it into a soluble insulin binder (sIB). The sIB, a 17 kDa protein, binds insulin with 38 nM affinity. The sIB competes with IR for insulin and reduces by more than 50% phosphorylation of AKT1 in HEK 293 T cells, with similar effects on IR autophosphorylation. The sIB represents a new tool for research of insulin binding and signaling properties.

Original language	English
Article number	151293
Journal	European Journal of Cell Biology
Volume	102
Issue number	2
DOIs	https://doi.org/10.1016/j.ejcb.2023.151293
State	Published - 1 Jun 2023
Externally published	Yes

Keywords

AKT
Insulin
Insulin receptor

ASJC Scopus subject areas

Pathology and Forensic Medicine
Histology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejcb.2023.151293

Cite this

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title = "Insulin receptor-inspired soluble insulin binder",

abstract = "The insulin receptor (IR) is a 320 kDa membrane receptor tyrosine kinase mediating the pleiotropic actions of insulin, leading to phosphorylation of several intracellular substrates including serine/threonine-protein kinase (AKT1), and IR autophosphorylation. Structural details of the IR have been recently revealed. A high-binding insulin site, L1 (Kd =2 nM), consists of two distant domains in the primary sequence of the IR. Our design simplified the L1 binding site and transformed it into a soluble insulin binder (sIB). The sIB, a 17 kDa protein, binds insulin with 38 nM affinity. The sIB competes with IR for insulin and reduces by more than 50\% phosphorylation of AKT1 in HEK 293 T cells, with similar effects on IR autophosphorylation. The sIB represents a new tool for research of insulin binding and signaling properties.",

keywords = "AKT, Insulin, Insulin receptor",

author = "Christopher Mendoza and Cameron Hanegan and Alek Sperry and Logan Vargas and Trevor Case and Benjamin Bikman and Dario Mizrachi",

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doi = "10.1016/j.ejcb.2023.151293",

language = "English",

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T1 - Insulin receptor-inspired soluble insulin binder

AU - Mendoza, Christopher

AU - Hanegan, Cameron

AU - Sperry, Alek

AU - Vargas, Logan

AU - Case, Trevor

AU - Bikman, Benjamin

AU - Mizrachi, Dario

PY - 2023/6/1

Y1 - 2023/6/1

N2 - The insulin receptor (IR) is a 320 kDa membrane receptor tyrosine kinase mediating the pleiotropic actions of insulin, leading to phosphorylation of several intracellular substrates including serine/threonine-protein kinase (AKT1), and IR autophosphorylation. Structural details of the IR have been recently revealed. A high-binding insulin site, L1 (Kd =2 nM), consists of two distant domains in the primary sequence of the IR. Our design simplified the L1 binding site and transformed it into a soluble insulin binder (sIB). The sIB, a 17 kDa protein, binds insulin with 38 nM affinity. The sIB competes with IR for insulin and reduces by more than 50% phosphorylation of AKT1 in HEK 293 T cells, with similar effects on IR autophosphorylation. The sIB represents a new tool for research of insulin binding and signaling properties.

AB - The insulin receptor (IR) is a 320 kDa membrane receptor tyrosine kinase mediating the pleiotropic actions of insulin, leading to phosphorylation of several intracellular substrates including serine/threonine-protein kinase (AKT1), and IR autophosphorylation. Structural details of the IR have been recently revealed. A high-binding insulin site, L1 (Kd =2 nM), consists of two distant domains in the primary sequence of the IR. Our design simplified the L1 binding site and transformed it into a soluble insulin binder (sIB). The sIB, a 17 kDa protein, binds insulin with 38 nM affinity. The sIB competes with IR for insulin and reduces by more than 50% phosphorylation of AKT1 in HEK 293 T cells, with similar effects on IR autophosphorylation. The sIB represents a new tool for research of insulin binding and signaling properties.

KW - AKT

KW - Insulin

KW - Insulin receptor

UR - https://www.scopus.com/pages/publications/85147596081

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DO - 10.1016/j.ejcb.2023.151293

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JF - European Journal of Cell Biology

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ER -

Insulin receptor-inspired soluble insulin binder

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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