The Acid-labile Subunit of the Serum Insulin-like Growth Factor-binding Protein Complexes

Abstract

The acid-labile subunit (ALS) is a glycosylated 85-kDa member of the leucine-rich repeat (LRR) protein superfamily and circulates in ternary complexes with the insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). These complexes are thought to regulate the serum IGFs by restricting IGF movement out of the circulation. However, little is known about how ALS binds to IGFBP-3 or -5, which link the IGFs to ALS. To investigate potential sites of interaction, the ALS structure has been modeled with the crystal structure of the LRR protein porcine ribonuclease inhibitor as a template. ALS is predicted to be a donut-shaped molecule with an internal diameter of 1.7 nm, an external diameter of 7.2 nm, and a thickness of 3.6 nm. These dimensions are supported by rotary shadowing electron microscopy of ALS. The internal face is lined with a substantial region of electronegative surface potential that could interact with the positively charged region on IGFBP-3 known to be involved in ALS binding. The model also predicts that three potential N-linked oligosaccharide sites within the LRR domain are clustered together, which may be important in light of recent studies showing ALS glycan involvement in complex formation with IGFBP-3.The majority of serum insulin-like growth factors (IGFs) 1 circulate within 130 -150-kDa ternary complexes containing either IGF-I or -II, IGF-binding protein (IGFBP)-3, and the acid-labile subunit (ALS), an 85-kDa glycoprotein. It is thought that the size of these complexes prevents IGF access to target cells, while free IGFs and IGFs in binary complexes with the IGFBPs can easily cross the capillary endothelial barrier. Furthermore, the ALS-containing complex significantly increases the serum half-lives of both the IGFs and IGFBP-3 and in this way maintains a circulating store of these molecules (1, 2). Therefore, the association of ALS to the IGF complex is an important event in serum IGF regulation. ALS binding is the limiting step in complex formation, since the affinity of ALS for the IGF⅐IGFBP-3 complex is up to 2000-fold less than the affinity of IGFBP-3 for the IGFs in physiological salt concentrations, pH and temperature (3). Recently, Twigg and Baxter (4) showed that ALS and the IGFs can also form a ternary complex in vitro with IGFBP-5 (which has high homology to IGFBP-3 in the ALS binding domain) and that this IGFBP-5 complex is found in low concentrations in serum.Although the structures of the IGFs have been solved (5, 6), the structures of the proteins which interact with and regulate the serum IGFs have not been elucidated. Therefore, it is not yet clear how ALS interacts physically with IGFBP-3 to form the ternary complexes. However, one major structural feature of ALS is that around 75% of its residues are ordered into 18 tandem repeats of 24 amino acids plus two partial repeats, all of which contain the consensus motif for the leucine-rich repeat (LRR) superfamily of proteins. (7). All the members of this superfamily are involved in protein-protein interactions...

Plasma androgens, IGF-1, body size, and prostate cancer risk: a synthetic review

“…IGFBP-5 binds IGF-1 with an even higher af®nity than IGFBP-3, and may also form a IGF-1/IGFBP-5/ALS complex. 87,88 Practically all of the remaining IGF-1 is bound to the IGFBPs-1, -2, -4 and -6, which have lower IGF-1 binding af®nities, and do not form complexes with ALS. 77,85,86 Therefore, a decrease in plasma IGFBP-3, or a relative transfer of IGF-1 from the IGFBPs-3 or -5 to smaller the IGFBPs not complexed with ALS is believed to result in increased IGF-1 availability to its tissue receptors.…”

Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit

“…The 150 kDa complexes cannot cross the capillary endothelial barrier, which prolongs the half-life of IGFs, IGFBP-3 and IGFBP-5, in the circulation (9)(10)(11). This seems to play an important role in the regulation of the bioavailability of IGFs to the tissue compartments.…”

“…About 75% of the mature protein consists of the consensus motif for the LRR superfamily of proteins. These leucine-rich domains organize ALS into a doughnut-shaped structure (11,12). Whereas ALS readily binds to binary complexes of IGFs and IGFBP-3, it does not interact directly with free IGFs and shows only a very low affinity for unliganded IGFBP-3 (13,14).…”

Measurement of the acid-labile subunit of the insulin-like growth factor binding protein complex in human serum: a comparison of four immunoassays

“…The majority of the IGFs in serum are associated with the most abundant binding protein, IGFBP-3, which can combine with another protein, known as the acid-labile subunit or ALS, to form heterotrimeric complexes containing IGF, IGFBP-3 and ALS . ALS is a leucine-rich glycoprotein of approximately 85 kDa, the protein core of which is predicted to be largely toroidal (Leong et al 1992, Janosi et al 1999b). It has recently been shown that ALS can also form similar ternary complexes with IGFBP-5 and IGFs (Twigg & Baxter 1998), although IGFBP-5 complexes would be expected to be relatively minor carriers of IGFs compared with IGFBP-3, due to the 5-to 10-fold lower serum IGFBP-5 concentration (Baxter & Martin 1986, Mohan et al 1995.…”