TY - JOUR T1 - Structural basis of integrin α6β4 interaction with the bullous pemphigoid antigen BP230 in hemidesmosomes JF - bioRxiv DO - 10.1101/402123 SP - 402123 AU - José A Manso AU - María Gómez-Hernández AU - Arturo Carabias AU - Noelia Alonso-García AU - Inés García-Rubio AU - Maaike Kreft AU - Arnoud Sonnenberg AU - José M de Pereda Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/08/31/402123.abstract N2 - Mechanical stability of epithelia requires firm attachment of the cells to the basement membrane via complexes named hemidesmosomes. Disorders that target hemidesmosomal proteins cause severe skin blistering diseases. In type I hemidesmosomes, present in the epidermis, integrin α6β4 is connected to intermediate filaments via plectin and BP230 (BPAG1e). To unravel the molecular basis of the BP230-β4 interaction, we first mapped their mutual binding sites and subsequently solved the crystal structure of a human BP230-β4 complex. BP230 binds to the fourth FnIII domain and in between the third and fourth FnIII domains of β4, which in turn form an inter-domain ionic clasp required for binding. Using DEER, we show that BP230-binding induces closure of the two FnIII domains. Disruption of the BP230-β4 interface prevents the recruitment of BP230 to hemidesmosomes in keratinocytes in culture, revealing a key role of the BP230-β4 interaction for the assembly of hemidesmosomes. Phosphomimetic substitutions of T1663 of β4, and T39 and S46 of BP230, disrupt binding, suggesting that the BP230-β4 interaction might be regulated by phosphorylation during hemidesmosome disassembly. ER -