The interaction of insulin-like growth factor-I with
the N-terminal domain of IGFBP-

The interaction of IGF-1 with the N-terminal domain of IGFBP-5

  Nicolette Peters '19 and Natalie Twitchell '19


I. Introduction

Insulin-like growth factors (IGF) are protein hormones with structural similarity to insulin, and they function in the body as regulators of cell division and differentiation.  IGF's mitogenic and anti-apoptotic abilities depend on its ability to bind with cell surface IGF-I receptors. This ability to bind with IGF-I receptors is regulated by Insulin-like growth factor-binding proteins (IGFBP) hold and bind to to regulate their biological interactions, releasing them upon proteolysis.  Additionally, IGFBPs transport IGFs, protect them from degradation, limit their receptor binding, and store their biologically inactive forms.

Furthermore, IGFs play a role in tumor growth and present themselves in cancers, neurological disorders, and bone disorders.  Because of this connection, high concentrations of IGFs can also indicate presences of cancer.  Therapeutic treatments can, therefore, target the IGF system to affect IGF binding with its binding proteins.  For example, tamoxifen may be used to induce production, inhibition, or degradation of IGFBPs in tumor cells.  Because of its biological implications with growth and various complicated illnesses, understanding the IGF system and its binding with binding proteins and receptors is crucial.

II. IGF Structure Compared to Insulin

Two-thirds of IGF structure consists of a single polypeptide chain, and the protein as a whole contains about seventy amino acids.  IGFs are structurally homologous to insulin (Figure 1), with about a 40% sequence similarity.  The first 29 residues of IGFs are homologous to the insulin B-chain, the next 12 residues are analogous to the insulin C-peptide, and the next 21 residues are homologus to the insulin A-chain.  Although IGF C-chains are analogous to a section of insulin, this section is unique to IGFs and is proteolytically removed after translation in other members of the insulin family. 

Figure 1. Insulin structure.

III. IGFBP Conserved Structure

IGFBPs are much larger than IGFs, consisting of about 216-289 residues.  , shown to the left, consists of 252 residues.  The IGFBP family shares common residues and structures, with the N-terminal and C-terminal regions appearing as the most conserved domains.  These domains are cysteine rich and form intra-domain bonds.  The N-terminal domain contains conserved cysteines which form disulfide bonds .  To the left, IGF-I binds with specifically the N-terminal binding domain of IGFBP-5, which is also called "mini-IGFBP-5."  Lastly, the central domain of IGFBPs, known as the "L-domain," is the least conserved region and accounts for most of the variety between individual IGFBPs.

IV. Binding Between IGF and IGFBP

While many IGFs and IGFBPs are known and studied, the interaction between specifically IGF-I and mini-IGFBP-5 is depicted here.  The N-terminal domain of IGFBPs binds with the highest affinity and is also able to bind insulin.  Hydrophobic and polar interactions combined with hydrogen bonds govern this binding.  These side chains form a "hydrophobic sandwich"and interweave with one another.  IGFBP-5 uses six hydrophobic residues, consisting of Leu and Val, to bind four hydrophobic side chains on IGF-I.  Using mutagenesis, researchers have found IGF-I residues to be the most important ones involved in IGF binding with IGFBP.  Additionally, govern and likely control IGFBP binding interactions since they are highly conserved across IGFBPs.

On the IGF-I side, Phe, Leu, and Glu are inserted into a side-chain pocket, or "hydrophobic sandwich", on IGFBP formed by Arg, Val, and Leu residues .  The in IGF makes direct contacts with the backbone and side chain as well as side chains in the N-terminal domain.  Hydrophilic and polar residues close this hydrophobic cluster of interactions.  in IGF-I form hydrogen bonds with mini-IGFBP-5's .  Additionally, Arg and Glu form hydrogen bonds .  Through a combination of polar and nonpolar interactions, IGF-I binds strongly with the N-terminal domain of IGFBP-5.

V. IGF Binding with Receptor IGF-1R

The interaction and binding between IFG-I and its receptor, IGF-1R, regulates many of IGF's mitogenic and anti-apoptotic characteristics.  IGF-I's receptor binding site consists of a solvent-exposed hydrophobic patch located on the from the IGFBP binding site.  aromatic residues guide this receptor binding.

Understanding IGF-I's structure helps explain inhibition of IGF binding with IGF-1R as a result of IGFBP-5 binding.  Excess of IGFBP-5 inhibits IGF-1R-IGF binding, although this inhibition is incomplete when only mini-IGFBP-5 is present.  IFG-I also continues to bind freely to its receptor even when exposed to high concentrations of mini-IGFBP-5.  This is due to the necessity of IGFBP's C-terminal domain for completely effective inhibition of IGF-1R-IGF binding.  Although the N-terminal domain of IGFBP has the highest binding affinity to IFGs, the C-terminal domain plays a larger role in regulation with the receptor.  Understanding the specific roles of IGFBPs with IGFs and their receptors can help researchers better understand how to alter these systems in biological systems and illnesses.

VI. References

Sala, A.; Capaldi, S.; Campagnoli, M. The Journal of Biological Chemistry 2005, 280, 29812-29819

ZCesoawski,W.; Beisel, H.-G.; Kamionka, M. The EMBO Journal 2001, 20 (14), 3638-3644.