Cystine Knot

 The cystine knot is a common protein motif that occurs in some protein structures. It incorporates an antiparallel b-sheet and three disulfide bonds, one of which passes through a ring formed by the other two disulfides (Fig. 1). Two families of cystine knot motifs have been identified. One is the growth factor cystine knot family (1, 2) that includes nerve growth factor, transforming growth factor b2, platelet derived growth factor, and human chorionic gonadotrophin. In this topology, the six cysteine residues (designated CI through CVI) form three disulfide bridges (CI-IV, CII-V, CIII-VI), with CI-IV passing through the ring formed by the disulfides of CII-V and CIII-VI. The size of the ring varies from 8 to 14 residues. The b-sheet is formed from four antiparallel b-strands. These cystine knot growth factors are all dimeric, but their dimer interfaces differ.

Figure 1. Schematic representation of the backbone structure of the growth factor cystine knot protein, nerve growth factor (4). b-Strands are shown as arrows, and the three disulfide bonds of the cystine knot are shown in gray, with the sulfur atoms depicted as gray spheres. The N- and C-termini are labeled. This figure was generated using Molscript (5(and Raster3D (6, 7).

The second group is the inhibitor cystine knot family (3) and includes the neurotoxin w-conotoxin GVIA and the uterotonic peptide kalata B1. The inhibitor cystine knot motif has the same disulfide bond pattern as the growth factor cystine knot, but in this case the knot is formed by CIII-VI passing through the ring formed by disulfides CI-IV and CII-V. The ring of the inhibitor cystine knot varies from 8 to 12 atoms, and the b-sheet is triple stranded and antiparallel.

References

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2. N. W. Isaacs (1995) Curr. Opin. Struct. Biol. 5, 391–395. 

3. P. K. Pallaghy, K. J. Nielsen, D. J. Craik, and R. S. Norton (1994) Protein Sci. 3, 1833–1839.

4. N. Q. McDonald et al. (1991) Nature 354, 411–414. 

5. P. J. Kraulis (1991) J. Appl. Crystallogr. 24, 946–950. 

6. E. A. Merritt and M. E. P. Murphy (1994) Acta Crystallogr. D50, 869–873. 

7. D. J. Bacon and W. F. Anderson (1988) J. Mol. Graphics 6, 219–222.