한빛사논문
- 조회355
Weidong An 1,4, Catherine Hall 2,4, Jie Li 1, Albert Hung 2, Jiayi Wu 2, Junhee Park 2, Liwei Wang 1, Xiao-chen Bai 1,3,* & Eunhee Choi 2,*
1Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
3Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4These authors contributed equally: Weidong An, Catherine Hall.
*Corresponding authors: correspondence to Xiao-chen Bai or Eunhee Choi
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.
논문정보
- Research article
- 2024년 03월 (BRIC 등록일 2024-03-27)
- 국외 연구진
- 생명과학 > 분자생물학
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