The acid-labile subunit of the serum insulin-like growth factor-binding protein complexes - Structural determination by molecular modeling and electron microscopy

The acid-labile subunit (ALS) is a glycosylated 85-kDa member of the leucin e-rich repeat (LRR) protein superfamily and circulates in ternary complexes with the insulin-like growth factors (IGFs) and their binding proteins (IG FBPs), These complexes are thought to regulate the serum IGFs by restrictin g IGF movement out of the circulation. However, little is known about how A LS binds to IGFBP-3 or -5, which link the IGFs to ALS, To investigate poten tial sites of interaction, the ALS structure has been modeled with the crys tal structure of the LRR protein porcine ribonuclease inhibitor as a templa te. ALS is predicted to be a donut-shaped molecule with an internal diamete r of 1.7 nm, an external diameter of 7.2 nm, and a thickness of 3.6 nm, The se dimensions are supported by rotary shadowing electron microscopy of ALS, The internal face is lined with a substantial region of electronegative su rface potential that could interact with the positively charged region on I GFBP-3 known to be involved in ALS binding. The model also predicts that th ree potential N-linked oligosaccharide sites within the LRR domain are clus tered together, which may be important in light of recent studies showing A LS glycan involvement in complex formation with IGFBP-3.