Structural basis for assembly and disassembly of the IGF/IGFBP/ALS ternary complex

Hyojin Kim, Yaoyao Fu, Ho Jeong Hong, Seong-Gyu Lee, Dong Sun Lee and Ho Min Kim ()
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Hyojin Kim: Korea Advanced Institute of Science and Technology (KAIST)
Yaoyao Fu: Center for Biomolecular & Cellular Structure, IBS
Ho Jeong Hong: Center for Biomolecular & Cellular Structure, IBS
Seong-Gyu Lee: Center for Biomolecular & Cellular Structure, IBS
Dong Sun Lee: Center for Biomolecular & Cellular Structure, IBS
Ho Min Kim: Korea Advanced Institute of Science and Technology (KAIST)

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Insulin-like growth factors (IGFs) have pleiotropic roles in embryonic and postnatal growth and differentiation. Most serum IGFs are bound in a ternary complex with IGF-binding protein 3 (IGFBP3) and acid-labile subunit (ALS), extending the serum half-life of IGFs and regulating their availability. Here, we report cryo-EM structure of the human IGF1/IGFBP3/ALS ternary complex, revealing the detailed architecture of a parachute-like ternary complex and crucial determinants for their sequential and specific assembly. In vitro biochemical studies show that proteolysis at the central linker domain of IGFBP3 induces release of its C-terminal domain rather than IGF1 release from the ternary complex, yielding an intermediate complex that enhances IGF1 bioavailability. Our results provide mechanistic insight into IGF/IGFBP3/ALS ternary complex assembly and its disassembly upon proteolysis for IGF bioavailability, suggesting a structural basis for human diseases associated with IGF1 and IGFALS gene mutations such as complete ALS deficiency (ACLSD) and IGF1 deficiency.

Date: 2022
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DOI: 10.1038/s41467-022-32214-2

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