The insulin-like growth factors (IGF-I and IGF-II) bind to specific binding
proteins in extracellular fluids with high affinity [1,2,3]. These IGF-binding
proteins (IGFBP) prolong the half-life of the IGFs and have been shown to
either inhibit or stimulate the growth promoting effects of the IGFs on cells
culture. They seem to alter the interaction of IGFs with their cell surface
receptors. The IGFBP family comprises six proteins (IGFBP-1 to -6) that bind
to IGFs with high affinity. The precursor forms of all six IGFBPs have
secretory signal peptides. All IGFBPs share a common domain organization and
also a high degree of similarity in their primary protein structure. The
highest conservation is found in the N- and C-terminal cysteine-rich regions.
Twelve conserved cysteines (ten in IGFBP-6) are found in the N-terminal
domain, and six are found in the C-terminal domain. Both the N- and C-terminal
domains participate in binding to IGFs, although the specific roles each of
these domains in IGF binding have not been decisively established. In general,
the strongest binding to IGFs is shown by amino-terminal fragments, which,
however bind to IGF with 10- to 1000-fold lower affinity than full length
IGFBPs. The central weakly conserved part (L domain) contains most of the
cleavage sites for specific proteases [4,5].
The N-terminal domain is ~80 residues in length and has an L-like structure
(see <PDB:1WQJ>). It can be divided into two subdomains that are connected by
a short stretch of amino acids. The two subdomains are perpendicular to each
other, creating the "L" shape for the whole N-terminal domain. The core of the
first subdomain presents a novel fold stabilized by a short two-stranded β
sheet and four disulfide bridges forming a disulfide bond ladder-like
structure. The β sheet and disulfide bridges are all in one plane, making
the structure appear flat from one side like a "palm" of a hand. The palm is
extended with a "thumb" segment in various IGFBPs. The thumb segment consists
of the very N-terminal residues and contains a consensus XhhyC motif, where h
is a hydrophobic amino acid and y is positively charged. The second subdomain
adopts a globular fold whose scaffold is secured by an inside packing of two
cysteines bridges stabilized by a three-stranded β sheet [4,5].
The following growth-factor inducible proteins are structurally related to
IGFBPs and could function as growth-factor binding proteins [6,7]:
Mouse protein cyr61 and its probable chicken homolog, protein CEF-10.
Human connective tissue growth factor (CTGF) and its mouse homolog, protein
Vertebrate protein NOV.
As a signature pattern we have used a conserved cysteine-rich region located
in the N-terminal IGFBP domain. We also developed a profile that covers the
entire IGFBP N-terminal domain.
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