VEGFA Structure

VEGF-A is a highly conserved, disulfide-bonded dimeric glycoprotein of Mr ~45kD. It shares low but significant sequence homology with platelet-derived growth factor (PDGF) and, like PDGF, has cysteines that form integral inter- and intra-chain bonds. Crystal structure reveals that the two chains that comprise VEGF-A are arranged in antiparallel fashion with binding sites at either end. Upon reduction, VEGF-A separates into its individual chains and loses all biological activity.

The human VEGF-A gene is located on the short arm of chromosome 6 and is differentially spliced to yield predominant isoforms that encode polypeptides of 206, 189, 165, and 121 amino acids in human cells (corresponding murine proteins are one amino acid shorter) (Figure 1). Other splice variants (183, 165b, 145) have also been described. The several major VEGF-A isoforms have distinct physical properties. VEGF-A120/1 is acidic, freely soluble, and does not bind heparin. By contrast, the 164/5 and 188/9 isoforms have increasing basic charge and bind heparin with increasing affinity; in fact, VEGF-A165 was originally purified on the basis of its affinity for heparin. Heparin, heparan sulfate, and heparinase all displace the larger VEGF-A isoforms from proteoglycan binding sites in tissues; proteases such as plasmin have a similar net effect, cleaving the C-terminal portion of bound VEGF-A to generate a biologically active peptide. In several situations in vivo, liberation of bound VEGF-A from cells or cell matrix is the necessary trigger that initiates angiogenic activity. The different VEGF-A isoforms have largely identical biological activities in vitro, but there is increasing evidence for distinctive functions in vivo; for example, mice

N-terminus

Plasmin cleavage signal seq

Exons

VEGF

VEGF

VEGF

VEGF

VEGFR-1 VEGFR-2 binding site binding site

Neuropilin binding site

Heparin binding site inding site /

signal seq

VEGFR-1 VEGFR-2 binding site binding site

Heparin binding site inding site /

Exons

1

2

3

4

5

6a

1 6b

7

8

___

1 1

_____

Figure 1 VEGF-A Gene Structure. VEGF-Ahas eight exons, the first of which encodes a hydrophobic leader sequence, typical of secreted proteins. The 206 amino acid VEGF-A isomer is encoded by all eight exons. VEGF-A189 lacks a portion of exon 6, whereas VEGF-A165, frequently the predominant isoform, lacks all of exon 6. VEGF-A121 lacks both exons 6 and 7. VEGF receptor and heparin binding sites are as indicated. [Republished with permission from Cross et al. (2003), Trends in Biochemical Sciences 28, 488.] (see color insert)

expressing only the 120 or 188 isoforms develop severe vascular anomalies.

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