A structural superfamily of growth factors containing a cystine knot motif

Abstract

Neil Q. McDonald and Wayne A. Hendrickson Department of Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute College of Physicians and Surgeons of Columbia University New York, New York 10032 The three-dimensional structures of proteins can provide important insights, sometimes unexpectedly, into the evo- lutionary relationships of proteins. Proteins may evolve from a common ancestor to the point at which they no longer share any significant overall sequence similarity (less than 20% identity), but their evolutionary relatedness may still be evident from a structural comparison. This is because those few invariant or conservatively replaced amino acid residues that are critical for the preservation of the three-dimensional structure can be identified from structural information. Locating such weaksignalsof relat- edness by sequence comparisons alone requires large numbers of sequences, whereas two related three- dimensional structures can be expected to show a good superposition of these invariant residues in topologically equivalent positions, despite great sequence divergence elsewhere. Polypeptide growth factors, a diverse group of regula- tory agents that control cell survival, proliferation, and dif- ferentiation, provide a good illustration of this phenome- non (Table 1). Nerve growth factor (NGF), transforming growth factor 82 (TGFj32), and platelet-derived growth fac- tor BB (PDGF-BB) have been found to adopt similar pro- tomeric structures that contain a motif we shall refer to as the cystine knot. These growth factors contain this motif and aconserved b-strand structure, arguing that they form a structural superfamily. The evolutionary and functional implications that arise from this observation, which is the focus of this minireview, are discussed here. The determination of the crystal structure of dimeric NGF revealed a novel three-dimensional fold. Each sub- unit consists of predominantly P-strand secondary struc- ture and an unusual clustering of three cystine bridges (McDonald et al., 1991). Subsequently, the structure of TGFj32 (Daopin et al., 1992a; Schlunegger and Griitter, 1992) showed a tertiary fold similar to NGF (Swindells, 1992; Murzin and Chothia, 1992). This observation has been confirmed by a structural comparison of the NGF and TGF82 molecules (Daopin et al., 1992b). The structure determination of PDGF-BB has provided another example of this structural fold (Oefner et al., 1992). Figure 1 shows a schematic summary of the three pro- tomer structures of NGF, TGFpP, and PDGF-BB that high- lights the common features characterizing the fold, partic- ularly the cystine knot motif (open circles) and two pairs of antiparallel 8 strands (labeled 81-84). In the NGF struc- ture, the disulfide bridges Cy~~-Cys~~ and Cys”-Cy~~~~ form a 1Cmembered ring through which the Cy~~~-Cys~ juncture passes. These three disulfide bridges have topo-