Structural basis for assembly and disassembly of the IGF/IGFBP/ALS ternary complex
Hyojin Kim1, Yaoyao Fu2, Ho Jeong Hong2
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
Nature Communications
|July 30, 2022
Summary
The study reveals the structure of the insulin-like growth factor 1 (IGF1)/IGF-binding protein 3 (IGFBP3)/acid-labile subunit (ALS) complex. Proteolysis of IGFBP3 enhances IGF1 availability, offering insights into IGF1 deficiency disorders.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Endocrinology
Background:
- Insulin-like growth factors (IGFs) are crucial for growth and differentiation.
- Serum IGFs circulate primarily in a ternary complex with IGF-binding protein 3 (IGFBP3) and acid-labile subunit (ALS).
- This complex extends IGF half-life and regulates bioavailability.
Purpose of the Study:
- To determine the cryo-electron microscopy (cryo-EM) structure of the human IGF1/IGFBP3/ALS ternary complex.
- To elucidate the mechanisms of ternary complex assembly and disassembly.
- To understand how proteolysis affects IGF1 bioavailability.
Main Methods:
- Cryo-electron microscopy (cryo-EM) for structural determination.
- In vitro biochemical assays to study complex assembly and proteolysis.
- Analysis of ternary complex architecture and assembly determinants.
Main Results:
- The detailed cryo-EM structure of the human IGF1/IGFBP3/ALS ternary complex was revealed.
- The structure displays a parachute-like architecture with specific assembly determinants.
- Proteolysis of IGFBP3's central linker releases its C-terminal domain, not IGF1, enhancing IGF1 bioavailability.
Conclusions:
- The study provides mechanistic insights into the assembly and proteolysis-driven disassembly of the IGF1/IGFBP3/ALS complex.
- The findings offer a structural basis for diseases linked to IGF1 and IGFALS gene mutations, such as complete ALS deficiency and IGF1 deficiency.
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