Integrin α6β4 Recognition of a Linear Motif of Bullous Pemphigoid Antigen BP230 Controls Its Recruitment to Hemidesmosomes

• Published in: Structure (London) Vol. 27; no. 6; pp. 952 - 964.e6
• Main Authors: Manso, José A., Gómez-Hernández, María, Carabias, Arturo, Alonso-García, Noelia, García-Rubio, Inés, Kreft, Maaike, Sonnenberg, Arnoud, de Pereda, José M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 04.06.2019
• Subjects: Amino Acid Sequence; Basement Membrane - metabolism; Binding Sites - genetics; cell adhesion; Crystallography, X-Ray; DEER; Dystonin - chemistry; Dystonin - genetics; Dystonin - metabolism; epithelia; Hemidesmosomes - genetics; Hemidesmosomes - metabolism; Humans; Integrin alpha6beta4 - chemistry; Integrin alpha6beta4 - genetics; Integrin alpha6beta4 - metabolism; intermediate filaments; keratinocytes; Keratinocytes - cytology; Keratinocytes - metabolism; Models, Molecular; Mutagenesis; Pemphigoid, Bullous - genetics; Pemphigoid, Bullous - metabolism; plakins; Protein Binding; Protein Domains; protein-protein interactions; SAXS; Sequence Homology, Amino Acid; DEER; cell adhesion; plakins; keratinocytes; epithelia; intermediate filaments; protein-protein interactions; SAXS
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2019.03.016

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 locked in place by an interdomain ionic clasp required for binding. Disruption of BP230-β4 binding prevents recruitment of BP230 to hemidesmosomes in human keratinocytes, revealing a key role of this interaction for hemidesmosome assembly. Phosphomimetic substitutions in β4 and BP230 destabilize the complex. Thus, our study provides insights into the architecture of hemidesmosomes and potential mechanisms of regulation. [Display omitted] •Mutual binding sites in integrin α6β4 and BP230 have been identified•Crystal structure of β4-BP230 complex has been solved•Binding of BP230 induces conformation change in β4 as observed by DEER•Binding of BP230 to β4 is necessary for recruitment of BP230 into hemidesmosomes BP230 connects the integrin α6β4 to intermediate filaments in hemidesmosomes. Manso et al. report the crystal structure of BP230 complexed to β4 and the conformational change in β4 caused by BP230. They identified residues important for binding and propose potential mechanisms of regulation of hemidesmosome assembly and disassembly.