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TITLE Structural basis for assembly and disassembly of the IGF/IGFBP/ALS ternary complex
AUTHOR Hyojin Kim, Yaoyao Fu, Ho Jeong Hong, Seong-Gyu Lee, Dong Sun Lee & Ho Min Kim
YEAR 2022
JOURNAL Nature Communications
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.

 
FULL ARTICLE https://www.nature.com/articles/s41467-022-32214-2
INSTRUMENT HPLC Detector FP-4025
KEYWORDS Cell growth, Cryoelectron microscopy, Growth factor signalling
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