Activation of the insulin receptor by insulin-like growth factor 2
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 struc...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46990-6 |
| _version_ | 1827310053196038144 |
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| author | Weidong An Catherine Hall Jie Li Albert Hung Jiayi Wu Junhee Park Liwei Wang Xiao-chen Bai Eunhee Choi |
| author_facet | Weidong An Catherine Hall Jie Li Albert Hung Jiayi Wu Junhee Park Liwei Wang Xiao-chen Bai Eunhee Choi |
| author_sort | Weidong An |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T19:53:34Z |
| format | Article |
| id | doaj.art-239ced1a90954917815111d3b2fd7c95 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T19:53:34Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-239ced1a90954917815111d3b2fd7c952024-03-24T12:26:31ZengNature PortfolioNature Communications2041-17232024-03-0115111710.1038/s41467-024-46990-6Activation of the insulin receptor by insulin-like growth factor 2Weidong An0Catherine Hall1Jie Li2Albert Hung3Jiayi Wu4Junhee Park5Liwei Wang6Xiao-chen Bai7Eunhee Choi8Department of Biophysics, University of Texas Southwestern Medical CenterDepartment of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Biophysics, University of Texas Southwestern Medical CenterDepartment of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Biophysics, University of Texas Southwestern Medical CenterDepartment of Biophysics, University of Texas Southwestern Medical CenterDepartment of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia UniversityAbstract 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.https://doi.org/10.1038/s41467-024-46990-6 |
| spellingShingle | Weidong An Catherine Hall Jie Li Albert Hung Jiayi Wu Junhee Park Liwei Wang Xiao-chen Bai Eunhee Choi Activation of the insulin receptor by insulin-like growth factor 2 Nature Communications |
| title | Activation of the insulin receptor by insulin-like growth factor 2 |
| title_full | Activation of the insulin receptor by insulin-like growth factor 2 |
| title_fullStr | Activation of the insulin receptor by insulin-like growth factor 2 |
| title_full_unstemmed | Activation of the insulin receptor by insulin-like growth factor 2 |
| title_short | Activation of the insulin receptor by insulin-like growth factor 2 |
| title_sort | activation of the insulin receptor by insulin like growth factor 2 |
| url | https://doi.org/10.1038/s41467-024-46990-6 |
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