한빛사논문
- 조회417
Liwei Wang1†, Catherine E. Hall2†, Emiko Uchikawa1‡, Dailu Chen3, Eunhee Choi2*, Xuewu Zhang4*, Xiao-chen Bai1,5*
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.
3Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
*Corresponding authors: Eunhee Choi, Xuewu Zhang, Xiao-chen Bai
†These authors contributed equally to this work.
‡Present address: Dubochet Center for Imaging, Lausanne, Switzerland
Abstract
Insulin is a hormone responsible for maintaining normal glucose levels by activating insulin receptor (IR) and is the primary treatment for diabetes. However, insulin is prone to unfolding and forming cross-β fibers. Fibrillation complicates insulin storage and therapeutic application. Molecular details of insulin fibrillation remain unclear, hindering efforts to prevent fibrillation process. Here, we characterized insulin fibrils using cryo-electron microscopy (cryo-EM), showing multiple forms that contain one or more of the protofilaments containing both the A and B chains of insulin linked by disulfide bonds. We solved the cryo-EM structure of one of the fibril forms composed of two protofilaments at 3.2-Å resolution, which reveals both the β sheet conformation of the protofilament and the packing interaction between them that underlie the fibrillation. On the basis of this structure, we designed several insulin mutants that display reduced fibrillation while maintaining native IR signaling activity. These designed insulin analogs may be developed into more effective therapeutics for type 1 diabetes.
논문정보
- Research article
- 2023년 09월 (BRIC 등록일 2023-09-18)
- 국외 연구진
- 생명과학 > 분자생물학
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