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Link to original content: https://www.ncbi.nlm.nih.gov/pubmed/21917115
Tying the knot: the cystine signature and molecular-recognition processes of the vascular endothelial growth factor family of angiogenic cytokines - PubMed Skip to main page content
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Review
. 2011 Nov;278(22):4304-22.
doi: 10.1111/j.1742-4658.2011.08350.x. Epub 2011 Oct 7.

Tying the knot: the cystine signature and molecular-recognition processes of the vascular endothelial growth factor family of angiogenic cytokines

Shalini Iyer  1 , K Ravi Acharya
Affiliations
Free PMC article
Review

Tying the knot: the cystine signature and molecular-recognition processes of the vascular endothelial growth factor family of angiogenic cytokines

Shalini Iyer et al. FEBS J. 2011 Nov.
Free PMC article

Abstract

The cystine-knot motif, made up of three intertwined disulfide bridges, is a unique feature of several toxins, cyclotides and growth factors, and occurs in a variety of species, including fungi, insects, molluscs and mammals. Growth factor molecules containing the cystine-knot motif serve as ligands for a diverse range of receptors and play an important role in extracellular signalling. This superfamily of polypeptides comprises several homodimeric and heterodimeric molecules that are central characters in both health and disease. Amongst these molecules are a group of proteins that belong to the vascular endothelial growth factor (VEGF) subfamily. The members of this family are known angiogenic factors that regulate processes leading to blood vessel formation in physiological and pathological conditions. The focus of the present review is on the structural characteristics of proteins that belong to the VEGF family and on signal-transduction pathways that become initiated via the VEGF receptors.

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Figures

Fig. 1
Fig. 1
Schematic representation of the three groups of cystine-knot proteins [107]: GFCKs, ICKs and CCKs. The cysteine residues are labelled I to VI and the disulfide bonds are shown as dotted lines.
Fig. 2
Fig. 2
Ribbon representation of the four GFCK prototypes [108]. The cystine-knot motif is shown in all four structures as a ball-and-stick model. The PDB codes for coordinates used are indicated in parentheses.
Fig. 3
Fig. 3
Sequence alignment of all human VEGF family proteins. The alignment was created using the program ALINE [109]. The amino acid residues have been coloured based on similarity. Identical residues are shaded black and residues of similar character are coloured in shades of grey. The cysteine residues that are involved in the formation of the knot are shaded yellow. They are numbered in order from N-terminus to the C-terminus. The three disulfide bridges are formed between Cys I and Cys VI, Cys III and Cys VII, and Cys V and Cys VIII.
Fig. 4
Fig. 4
A schematic representation of the various receptors characterized for the members of the VEGF family of cystine-knot proteins [107]. VEGFR-1 (fetal murine sarcoma-like tyrosine kinase (Flt)-1), VEGFR-2 [kinase-insert domain receptor (KDR)] and VEGFR-3 (Flt-4) are tyrosine kinase receptors. NRP-1 and NRP-2 (neuropilins) belong to the family of semaphorin receptors. HSPGs act as binding partners for some of the isoforms of the VEGF proteins. The receptors have been coloured individually. The arrows point to the ligands that bind each of these receptors and these have been coloured according to the receptor they represent.
Fig. 5
Fig. 5
Genomic (human, denoted with the prefix ‘h’) organization and alternative splice forms of VEGF-A, VEGF-B and PlGF [107]. The exons coding for the PDGF homology domain (orange), heparin-binding domain (dark blue) and NRP-binding domain (light blue) are indicated in the figure. The exons are shown as oval, shaded structures, whereas the introns are represented by lines. The sizes and lengths of the exons and introns have not been drawn to scale.
Fig. 6
Fig. 6
Genomic (human) organization of VEGF-C and VEGF-D precursor proteins [107]. The PDGF homology domain (shown in orange) in the precursor proteins is covalently linked to the N-terminal and the C-terminal pro-peptides via disulfide bonds (S-S). The amino acid positions for each of the three proteolytically processed domains are shown in parentheses.
Fig. 7
Fig. 7
Modification of the EC response to VEGF-A (green) by PlGF (magenta) during pathological conditions [107]. When the concentration of PlGF is low, both VEGFR-1 (purple) and VEGFR-2 (orange) bind VEGF-A and normal angiogenesis occurs (A). However, during pathological conditions (B and C), there is an increase in the concentration of PlGF, which displaces VEGF-A from VEGFR-1 and thereby increases the bioavailability of VEGF-A for VEGFR-2 [59].
Fig. 8
Fig. 8
Ribbon representation of the members belonging to the VEGF family of growth factors [108]. VEGF-A is coloured green (2VPF; [61]), VEGF-B is coloured orange-yellow (2C7W; [63]), VEGF-C is coloured bright orange (2X1W; [74]), VEGF-D is coloured pale green (2XV7; [64]), VEGF-E is coloured pale cyan (2GNN; [65]), VEGF-F is coloured dark blue (2WQ8; [50]) and PlGF-1 is coloured magenta (1FZV; [62]).
Fig. 9
Fig. 9
Ribbon representation of the different receptor–growth factor complexes [108]. The top panel shows the side view of the complex while the bottom panel shows the front view. The receptor and the growth factor molecules have been labelled. VEGFR-1 is shown in light blue, whereas VEGFR-2 is coloured dark blue. VEGF-A is coloured green, VEGF-B is coloured orange-yellow, VEGF-C is coloured bright orange and PlGF-1 is coloured in magenta. The structures shown are VEGF-A8–109•VEGFR-1D2 complex (1FLT; [67]), VEGF-B10–108•VEGFR-1D2 complex (2XAC; [72]), PlGF-1•VEGFR-1D2 complex (1RV6; [73]), and VEGF-C•VEGFR-2D2D3 complex (2X1W; [74]).
Fig. 10
Fig. 10
Ribbon representation of the different antibody–growth factor complexes [108]. The top panel shows the side view of the complex while the bottom panel shows the front view. The antibody and the growth factor molecules have been labelled. The different generations of the VEGF-A-binding Fab molecules are shown in different shades of red, whereas Fab-binding VEGF-B is coloured marine blue. VEGF-A is coloured green and VEGF-B is coloured orange-yellow. The structures shown are of the complexes of VEGF-A8–109 with Fab-12 (1BJ1; [68]), Fab-Y0317 (1CZ8; [69]) and Fab-G6 (2FJG; [70]), and of VEGF-B with Fab-2H10 (2VWE; [71]).
Fig. 11
Fig. 11
Schematic representation of the molecular players involved in angiogenesis signalling mediated by the interaction of VEGF-A with VEGFR-2 [107]. The text includes all the references that were used to make the figure. DAG, diacyly glycerol; eNOS, endothelial nitric oxide synthase; Grb2, growth factor receptor-bound protein 2; MEK, MAPK/ERK pathway; PKB, protein kinase B; Raf, rapidly accelerated fibrosarcoma; Ras, RAt sarcoma; Sos, son of sevenless.
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References

    1. Murray-Rust J, McDonald NQ, Blundell TL, Hosang M, Oefner C, Winkler F, Bradshaw RA. Topological similarities in TGF-beta 2, PDGF-BB and NGF define a superfamily of polypeptide growth factors. Structure. 1993;1:153–159. - PubMed
    1. Pallaghy PK, Nielsen KJ, Craik DJ, Norton RS. A common structural motif incorporating a cystine knot and a triple-stranded beta-sheet in toxic and inhibitory polypeptides. Protein Sci. 1994;3:1833–1839. - PMC - PubMed
    1. Vitt UA, Hsu SY, Hsueh AJ. Evolution and classification of cystine knot-containing hormones and related extracellular signaling molecules. Mol Endocrinol. 2001;15:681–694. - PubMed
    1. Holbourn KP, Acharya KR, Perbal B. The CCN family of proteins: structure-function relationships. Trends Biochem Sci. 2008;33:461–473. - PMC - PubMed
    1. Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime H, Sato M. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene. 1990;5:519–524. - PubMed

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