Abstract
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.
Highlights
Most cellular processes depend on the formation of interactions between cells and the extracellular matrix (ECM)
Rhodocetin (RC) is a heterotetrameric protein found in the venom of the Malayan pit viper (C. rhodostoma)
RC binds α2β1 integrin, the key protein required for collagen-mediated platelet aggregation
Summary
Most cellular processes depend on the formation of interactions between cells and the extracellular matrix (ECM). Key facilitators of these interactions are the integrins. They consist of 2 subunits, α and β, each of which has multiple isoforms [1,2]. The different subunit composition between integrins determines their ligand-binding specificity and functionality. Integrins are cell adhesion molecules, which are involved in a broad range of cell functions, such as proliferation, differentiation, adhesion, and migration. Α2β1 integrin has become a prominent target in drug research [12,13,14]
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