Abstract
Mechanical stability of epithelia requires firm attachment to the basement membrane via hemidesmosomes. Dysfunction of hemidesmosomal proteins causes severe skin blistering diseases. Two plakins, plectin and BP230 (BPAG1e), link the integrin α6β4 to intermediate filaments in epidermal hemidesmosomes. Here, we show that a linear sequence within the isoform-specific N-terminal region of BP230 binds to the third and fourth FnIII domains of β4. The crystal structure of the complex and mutagenesis analysis revealed that BP230 binds between the two domains of β4. BP230 induces closing of the two FnIII domains that are looked in place by an inter-domain ionic clasp required for binding. Disruption of the BP230-β4 interface prevents the recruitment of BP230 to hemidesmosomes in human keratinocytes, revealing a key role of the BP230-β4 interaction for hemidesmosome assembly. Our study provides insights into the molecular mechanisms of hemidesmosome architecture and regulation.
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