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Dramatic and concerted conformational changes enable rhodocetin to block α2β1 integrin selectively
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نویسنده
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eble j.a. ,mcdougall m. ,orriss g.l. ,niland s. ,johanningmeier b. ,pohlentz g. ,meier m. ,karrasch s. ,estevão-costa m.i. ,martins lima a. ,stetefeld j.
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منبع
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plos biology - 2017 - دوره : 15 - شماره : 7
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چکیده
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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. © 2017 eble et al.
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آدرس
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institute of physiological chemistry and pathobiochemistry,university of münster,münster, Germany, departments of chemistry & microbiology,university of manitoba,winnipeg,mb, Canada, departments of chemistry & microbiology,university of manitoba,winnipeg,mb, Canada, institute of physiological chemistry and pathobiochemistry,university of münster,münster, Germany, institute of physiological chemistry and pathobiochemistry,university of münster,münster, Germany, institute of hygiene,university of münster,münster, Germany, departments of chemistry & microbiology,university of manitoba,winnipeg,mb, Canada, departments of chemistry & microbiology,university of manitoba,winnipeg,mb, Canada, institute of physiological chemistry and pathobiochemistry,university of münster,münster, Germany, institute of physiological chemistry and pathobiochemistry,university of münster,münster, Germany, departments of chemistry & microbiology,university of manitoba,winnipeg,mb, Canada
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Authors
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