Activation of the insulin receptor by insulin-like growth factor 2

Weidong An, Catherine Hall, Jie Li, Albert Hung, Jiayi Wu, Junhee Park, Liwei Wang, Xiao-chen Bai () and Eunhee Choi ()
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Weidong An: University of Texas Southwestern Medical Center
Catherine Hall: Columbia University
Jie Li: University of Texas Southwestern Medical Center
Albert Hung: Columbia University
Jiayi Wu: Columbia University
Junhee Park: Columbia University
Liwei Wang: University of Texas Southwestern Medical Center
Xiao-chen Bai: University of Texas Southwestern Medical Center
Eunhee Choi: Columbia University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin’s function. However, the molecular mechanism underlying IGF2-induced IR activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform IR (IR-B) in both the inactive and IGF2-bound active states, and short isoform IR (IR-A) in the IGF2-bound active state. Under saturated IGF2 concentrations, both the IR-A and IR-B adopt predominantly asymmetric conformations with two or three IGF2s bound at site-1 and site-2, which differs from that insulin saturated IR forms an exclusively T-shaped symmetric conformation. IGF2 exhibits a relatively weak binding to IR site-2 compared to insulin, making it less potent in promoting full IR activation. Cell-based experiments validated the functional importance of IGF2 binding to two distinct binding sites in optimal IR signaling and trafficking. In the inactive state, the C-terminus of α-CT of IR-B contacts FnIII-2 domain of the same protomer, hindering its threading into the C-loop of IGF2, thus reducing the association rate of IGF2 with IR-B. Collectively, our studies demonstrate the activation mechanism of IR by IGF2 and reveal the molecular basis underlying the different affinity of IGF2 to IR-A and IR-B.

Date: 2024
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DOI: 10.1038/s41467-024-46990-6

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