Four recent crystal structures of growth factors--nerve growth factor, transforming growth factor-beta, platelet-derived growth factor, and human chorionic gonadotropin--from four separate superfamilies revealed that these proteins are structurally related and share a common overall topology [1]. These proteins have very little sequence homology, but they all have an unusual arrangement of six cysteines linked to form a "cystine-knot" conformation. The active forms of these proteins are dimers, either homo- or heterodimers [2]. Because of their shape, there appears to be an intrinsic requirement for the cystine-knot growth factors to form dimers. This extra level of organization increases the variety of structures built around this simple structural motif [3].
1. McDonald N.Q. and Hendrickson W.A.
A structural superfamily of growth factors containing a cystine knot motif.
Cell 73: 421- 424 (1993) [PubMed: 8490958 ]
2. Sun P.D. and Davies D.R.
The cystine-knot growth-factor superfamily.
Annu. Rev. Biophys. Biomol. Struct. 24: 269- 291 (1995) [PubMed: 7663117 ]
3. Isaacs N.W.
Cystine knots.
Curr. Opin. Struct. Biol. 5: 391- 395 (1995) [PubMed: 7583638 ]
From IPR006207:
This domain is found at the C-terminal of glycoprotein hormones and various extracellular proteins. It is believed to be involved in disulphide-linked dimerisation.
1. The modular architecture of a new family of growth regulators related to connective tissue growth factor. Bork P; FEBS lett 1993;327:125-130.
From IPR006208:
The crystal structures of several proteins have been reported as having unusual folds, involving intramolecular disulphide bridges. In transforming growth factor-beta 2 (TGF-beta2) [1], platelet- derived growth factor (PDGF), nerve growth factor (NGF) [2] and human chorionic gonadotropin (hCG) [3], six conserved cysteines (I to VI in sequence order) form three disulphide links arranged in a knot-like topology. Cystines [II-V] and [III-VI] form a ring of eight amino acids through which the remaining disulphide bond (Cys[I-IV]) penetrates.
A similar knotted arrangement of disulphide bonds has been noted in the structures of some enzyme inhibitors and neurotoxins that bind to voltage- gated Ca2+ channels [4]. In those sequences, however, the cystine topology differs. Cys[III-VI] penetrates a macrocyclic ring formed by Cys[I-IV] and Cys[II- V]. Thus, cystine knots fall into two structural classes: growth factor type and inhibitor-like cystine knots [5].
All growth factor cystine knots structures have similar topology, with two distorted beta-hairpin loops "above" the knot and a single loop "below". The sizes of the hairpin loop vary significantly.
1. Schlunegger M.P. , Gruetter M.G.
An unusual feature revealed by the crystal structure at 2.2 A resolution of human transforming factor-beta2.
Nature 358: 430- 434 (1992) [PubMed: 1641027 ]
2. McDonald N.W. , Lapatto R. , Murray-Rust J. , Gunning J. , Wlodawer A. , Blundell T.L.
New protein fold revealed by a 2.3 A resolution crystal structure of nerve growth factor.
Nature 354: 411- 413 (1991) [PubMed: 1956407 ]
3. Lapthorn A.J. , Harris D.C. , Littlejohn A. , Lustbader J.W. , Canfield R.E. , Machin K.J. , Morgan F.J. , Isaacs N.W.
Crystal structure of human chorionic gonadotropin.
Nature 369: 455- 461 (1994) [PubMed: 8202136 ]
4. Pallaghy P.K. , Nielsen K.J. , Craik D.J. , Norton R.S.
A common structural motif incorporating a cystine knot and a triple-stranded beta-sheet in toxic and inhibitory polypeptides.
Protein Sci. 3: 1833- 1839 (1994) [PubMed: 7849598 ]
5. Isaacs N.W.
Cystine knots.
Curr. Opin. Struct. Biol. 5: 391- 395 (1995) [PubMed: 7583638 ]