Heparin Binding Domain of VEGF

The enhanced biological activity of the longer VEGF isoforms has recently been attributed to the formation of ternary complexes with VEGFR-2 and neuropilin [5]. The neuropilins are receptors for the class 3 semaphorins and participate in the guidance of growing axons to their targets. Their coreceptor function for VEGF (and PlGF) is mediated through the heparin-binding domain of these isoforms [6], resulting in enhanced affinity of VEGF for VEGFR-2 [7]. Neuropilin-1 also binds directly to flt1, in an interaction that antagonizes binding of VEGF, suggesting a role for flt1 as a negative regulator of angiogenesis [7].

The three-dimensional structure of the 55-residue heparin-binding domain of the longer VEGF isoforms consists of a novel heparin-binding fold that can be divided into two smaller subdomains, each having a short, anti-parallel P-sheet and two disulfide bonds [8] (Fig. 1A). The C-terminal

*Current address: Department of Protein Engineering, Genentech, Inc., South San Francisco, California

Copyright © 2003, Elsevier Science (USA).

Handbook of Cell Signaling, Volume 1 285 All rights reserved.

Figure 1 Three-dimensional structure of the domains of VEGF165, with the backbone rendered as ribbons and disulfide bonds as a ball and stick. (A) NMR structure of heparin-binding domain [8]. (B) Crystal structure of the receptor-binding domain [9].

subdomain contains a short helical segment that packs against the P-sheet. One side of this subdomain together with an adjacent loop stemming from the N-terminal half carries the majority of positively charged residues, and the resulting positively charged surface is believed to be responsible for the heparin-binding functionality [8].

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