Vipera lebetina venom contains two disintegrins inhibiting laminin-binding β1 integrins

Johannes A. Eble, Peter Bruckner, Ulrike Mayer

    Research output: Contribution to journalArticlepeer-review

    Abstract

    To explain the myotoxic effects of snake venoms, we searched for inhibitors of α7β11 integrin, the major laminin-binding integrin in skeletal muscle. We discovered two inhibitors in the venom of Vipera lebetina. One of them, lebein-1 (known as lebein), has already been proposed to be a disintegrin because of its RGD-containing primary sequence. The other, lebein-2, is a novel protein that also interacts firmly with α3β1, α6β1, and α7β1 integrins, but not with the collagen-binding α1β1 and α2β1 integrins. Ligand binding of laminin-recognizing β1 integrins was efficiently blocked by both lebein-1 and lebein-2. In cell attachment assays, lebein-1 and lebein-2 inhibited myoblast attachment not only to laminin, but also to fibronectin. However, neither lebein-1 nor lebein-2 interacted with α7β1 integrin in an RGD-dependent manner, similar to the interaction of the laminin with a7β1 integrin. Identical divalent cation dependence of integrin binding to laminin and to either of the two inhibitors and their mutually exclusive binding suggest that both lebein-1 and lebein-2 interact with the ligand-binding site of laminin-binding β1 integrins by mimicking the yet unknown integrin-binding structure of laminins. Like lebein-1, lebein-2 is a soluble heterodimeric disintegrin of low molecular mass. Together with membrane-bound ADAM-2 and ADAM-9, the two inhibitors seem to form a small group of disintegrins that can bind to laminin-binding β1 integrins. Because of their inhibitory capability both in vitro and in vivo, lebein-1 and lebein-2 may be valuable tools in influencing laminin-induced, integrin-mediated cell functions such as cell anchorage, migration, and mechanical force transduction on laminin-rich basement membranes.
    Original languageEnglish
    Pages (from-to)26488-26496
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume278
    Issue number29
    DOIs
    Publication statusPublished - 18 Jul 2003

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