Isolation of a funnel-web spider polypeptide with homology to mamba intestinal toxin 1 and the embryonic head inducer Dickkopf-1

We have isolated and determined the amino acid sequence of a novel peptide component from the venom of the Australian funnel-web spider Hadronyche ver suta. This 68-residue toxin, ACTX-Hvf17, does not function like classical n eurotoxins in modulating ion channel function as evidenced by its lack of i nsecticidal activity and its inability to affect vertebrate smooth or skele tal muscle contractility. The peptide shows significant sequence homology w ith mamba intestinal toxin 1 (MIT1) and to a lesser extent with a variety o f colipases. The strong structural homology between MIT1 and porcine colipa se leads us to propose that ACTX-Hvf17 also adopts the MIT1/colipase three- dimensional fold. However, we show that ACTX-Hvf17 has no colipase activity and does not stimulate muscle contractility like MIT1. We also show that M IT1 and ACTX-Hvf17 display significant sequence homology with the C-termina l cysteine-rich domain of the Dickkopf-1 family of proteins that induce hea d formation in developing embryos, which leads us to propose that this doma in of Dickkopf-1 also adopts the MIT1/colipase fold. (C) 1999 Elsevier Scie nce Ltd. All rights reserved.