8U4C

Cryo-EM structure of long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation.

8U4C の概要

• エントリーDOI: 10.2210/pdb8u4c/pdb
• EMDBエントリー: 41878
• 分子名称: Insulin receptor, Insulin-like growth factor II (2 entities in total)
• 機能のキーワード: insulin receptor, igf2, rtk, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 393718.25

構造登録者

An, W.,Hall, C.,Li, J.,Huang, A.,Wu, J.,Park, J.,Bai, X.C.,Choi, E. (登録日: 2023-09-10, 公開日: 2024-03-27, 最終更新日: 2024-11-06)

主引用文献

An, W.,Hall, C.,Li, J.,Hung, A.,Wu, J.,Park, J.,Wang, L.,Bai, X.C.,Choi, E.
Activation of the insulin receptor by insulin-like growth factor 2.
Nat Commun, 15:2609-2609, 2024

PubMed 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.

PubMed: 38521788
DOI: 10.1038/s41467-024-46990-6

実験手法

ELECTRON MICROSCOPY (3.6 Å)