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.
Highlights
The insulin-like growth factor binding protein (IGFBP) family consists of six structurally similar proteins (IGFBP-1 to -6), which bind insulin-like growth factors (IGFs) with high affinity (Firth and Baxter, 2002)
A complex picture has emerged of IGFBPs as multi-functional www.frontiersin.org proteins able to interact with a broad range of proteins and GAGs. These interactions confer on the IGFBPs the ability to modulate IGF actions and/or to influence IGF-independent actions, such as ECM and cell membrane binding leading to cell migration
An understanding of these molecular interactions has allowed researchers to probe the role of IGFBPs in normal growth and development as well as in disease
Summary
The insulin-like growth factor binding protein (IGFBP) family consists of six structurally similar proteins (IGFBP-1 to -6), which bind insulin-like growth factors (IGFs) with high affinity (Firth and Baxter, 2002). Two mechanisms of IGF release have been identified, one involving extracellular matrix (ECM) binding and the other IGFBP proteolysis (Firth and Baxter, 2002). Both of these processes lower the affinity of IGFBPs for IGFs and increase the local concentration of bioactive IGF. Almost all IGFBPs have been shown to have IGF-independent actions (Bach et al, 2005; Wheatcroft and Kearney, 2009) These are a consequence of their ability to enter cells and locate to the nucleus as well as their interaction with ECM components, integrins, or other binding partners. IGF-independent actions are much less well understood than IGF-dependent actions
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