Insulin-Like Growth Factor Binding Proteins: A Structural Perspective

Abstract

Insulin-like growth factor binding proteins (IGFBP-1 to -6) bind insulin-like growth factors-I and -II (IGF-I and IGF-II) with high affinity. These binding proteins maintain IGFs in the circulation and direct them to target tissues, where they promote cell growth, proliferation, differentiation, and survival via the type 1 IGF receptor. IGFBPs also interact with many other molecules, which not only influence their modulation of IGF action but also mediate IGF-independent activities that regulate processes such as cell migration and apoptosis by modulating gene transcription. IGFBPs-1 to -6 are structurally similar proteins consisting of three distinct domains, N-terminal, linker, and C-terminal. There have been major advances in our understanding of IGFBP structure in the last decade and a half. While there is still no structure of an intact IGFBP, several structures of individual N- and C-domains have been solved. The structure of a complex of N-BP-4:IGF-I:C-BP-4 has also been solved, providing a detailed picture of the structural features of the IGF binding site and the mechanism of binding. Structural studies have also identified features important for interaction with extracellular matrix components and integrins. This review summarizes structural studies reported so far and highlights features important for binding not only IGF but also other partners. We also highlight future directions in which structural studies will add to our knowledge of the role played by the IGFBP family in normal growth and development, as well as in disease.

Rapid molecular evolution across amniotes of the IIS/TOR network

“…IGF binding proteins regulate the ability of hormones to activate receptors through steric hindrance, thereby limiting the bioavailability of IGF1 and IGF2 to initiate the IIS/TOR signaling cascade (49). Intriguingly, we found that many reptile species appear to have truncated or missing N-terminal domains across the IGFBPs that would decrease IGF binding affinity.…”

“…IGF binding proteins bind to IGF1 and IGF2 in the bloodstream to regulate their bioavailability (48,49). These IGFBPs are characterized by N-and C-terminal domains that cooperate to bind IGFs; protease cleavage separating these domains decreases affinity to IGFs.…”

“…Furthermore, in examining the three N-terminal amino acids that are conserved across all binding proteins in humans (49), only one of these amino acids was conserved in only two snake species in IGFBP6, although all three sites were conserved across the reptile IGFBP2-5. For those amino acids important for binding IGFs and specific to IGFBP6 (49), only 7 of 12 are conserved in reptiles.…”

Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions

“…Both mutagenesis studies and structural determination by NMR and X-ray crystallography have revealed that high-affinity IGF binding involves residues in both the amino-and carboxy-terminal domains (Baxter 2000;Forbes et al 2012). Two of the six IGFBPs (IGFBP-3 and IGFBP-5) form complexes in the circulation that contain either IGF-I or IGF-II, and a third protein, the acid-labile subunit or ALS (encoded by the IGFALS gene).…”

Pregnancy-associated Plasma Protein A (PAPP-A) Modulates the Early Developmental Rate in Zebrafish Independently of Its Proteolytic Activity

“…Other probes used were ntla (cb240), myogenin (cb553), emx3 (eu682), and eng2a (eu759). 3 Whole Mount Immunohistochemistry-Embryos were fixed in 4% PFA in PBS for 1 h of shaking at room temperature. Fixed embryos were washed three times for 5 min each time in PBT (PBS ϩ 1% Triton X-100), blocked in PBT ϩ 10% goat serum for 1 h at room temperature, washed three times for 5 min each time in PBT, incubated with Ab-F59 cell supernatant (Developmental Studies Hybridoma Bank, Santa Cruz Biotechnology, Inc.) diluted 1:10 in PBT ϩ 1% goat serum overnight at 4°C, washed three times for 5 min each time in PBT, incubated with Alexa Fluor 488 goat anti-mouse IgG (Invitrogen) diluted 1:400 in PBT ϩ 1% goat serum for 3 h at room temperature, and washed overnight in PBT with three buffer changes.…”