EMD-43280

Single-particle
3.8 Å
EMD-43280 Deposition: 06/01/2024
Map released: 27/03/2024
Last modified: 23/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-43280

Cryo-EM structure of short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation.

EMD-43280

Single-particle
3.8 Å
EMD-43280 Deposition: 06/01/2024
Map released: 27/03/2024
Last modified: 23/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation.
Fitted models: 8vjc (Avg. Q-score: 0.321)

Deposition Authors: An W , Hall C , Li J , Huang A, Wu J , Park J , Bai XC , Choi E
Activation of the insulin receptor by insulin-like growth factor 2.
An W , Hall C , Li J , Hung A , Wu J , Park J , Wang L , Bai XC , Choi E
(2024) Nat Commun , 15 , 2609 - 2609
PUBMED: 38521788
DOI: doi:10.1038/s41467-024-46990-6
ISSN: 2041-1723
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.