Dramatic and concerted conformational changes enable rhodocetin to block α2β1 integrin selectively.
| Autor: | Johannes A Eble, Matthew McDougall, George L Orriss, Stephan Niland, Benjamin Johanningmeier, Gottfried Pohlentz, Markus Meier, Simone Karrasch, Maria Inacia Estevão-Costa, Augusto Martins Lima, Jörg Stetefeld |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | PLoS Biology, Vol 15, Iss 7, p e2001492 (2017) |
| Druh dokumentu: | article |
| ISSN: | 1544-9173 1545-7885 |
| DOI: | 10.1371/journal.pbio.2001492 |
| Popis: | The collagen binding integrin α2β1 plays a crucial role in hemostasis, fibrosis, and cancer progression amongst others. It is specifically inhibited by rhodocetin (RC), a C-type lectin-related protein (CLRP) found in Malayan pit viper (Calloselasma rhodostoma) venom. The structure of RC alone reveals a heterotetramer arranged as an αβ and γδ subunit in a cruciform shape. RC specifically binds to the collagen binding A-domain of the integrin α2 subunit, thereby blocking collagen-induced platelet aggregation. However, until now, the molecular basis for this interaction has remained unclear. Here, we present the molecular structure of the RCγδ-α2A complex solved to 3.0 Å resolution. Our findings show that RC undergoes a dramatic structural reorganization upon binding to α2β1 integrin. Besides the release of the nonbinding RCαβ tandem, the RCγ subunit interacts with loop 2 of the α2A domain as result of a dramatic conformational change. The RCδ subunit contacts the integrin α2A domain in the "closed" conformation through its helix C. Combined with epitope-mapped antibodies, conformationally locked α2A domain mutants, point mutations within the α2A loop 2, and chemical modifications of the purified toxin protein, this molecular structure of RCγδ-α2A complex explains the inhibitory mechanism and specificity of RC for α2β1 integrin. |
| Databáze: | Directory of Open Access Journals |
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