Dramatic and concerted conformational changes enable rhodocetin to block α2ß1 integrin selectively.
PLoS Biol
; 15(7): e2001492, 2017 Jul.
Article
em En
| MEDLINE
| ID: mdl-28704364
ABSTRACT
The collagen binding integrin α2ß1 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 αß 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 α2ß1 integrin. Besides the release of the nonbinding RCαß 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 α2ß1 integrin.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Venenos de Crotalídeos
/
Integrina alfa2beta1
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
PLoS Biol
Ano de publicação:
2017
Tipo de documento:
Article