Integrin a6ß4 recognition of a linear motif of bullous pemphigoid antigen BP230 controls its recruitment to hemidesmosomes

Manso, José A. ; Gómez-Hernández, María ; Carabias, Arturo ; Alonso-García, Noelia ; García-Rubio, Inés (Universidad de Zaragoza) ; Kreft, Maaike ; Sonnenberg, Arnoud ; Pereda, José M. de

Resumen: 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 a6ß4 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 ß4. The crystal structure of the complex and mutagenesis analysis revealed that BP230 binds between the two domains of ß4. BP230 induces closing of the two FnIII domains that are locked in place by an interdomain ionic clasp required for binding. Disruption of BP230-ß4 binding prevents recruitment of BP230 to hemidesmosomes in human keratinocytes, revealing a key role of this interaction for hemidesmosome assembly. Phosphomimetic substitutions in ß4 and BP230 destabilize the complex. Thus, our study provides insights into the architecture of hemidesmosomes and potential mechanisms of regulation.

Idioma: Inglés

DOI: 10.1016/j.str.2019.03.016

Año: 2019

Publicado en: Structure 27, 6 (2019), 952-964.e6
ISSN: 0969-2126

Factor impacto JCR: 4.862 (2019)

Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 64 / 296 = 0.216 (2019) - Q1 - T1
Categ. JCR: BIOPHYSICS rank: 9 / 71 = 0.127 (2019) - Q1 - T1
Categ. JCR: CELL BIOLOGY rank: 61 / 194 = 0.314 (2019) - Q2 - T1

Factor impacto SCIMAGO: 2.786 - Structural Biology (Q1) - Molecular Biology (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/E35-20R
Financiación: info:eu-repo/grantAgreement/EC/FP7/283570/EU/Transnational access and enhancement of integrated Biological Structure determination at synchrotron X-ray radiation facilities/BIOSTRUCT-X
Financiación: info:eu-repo/grantAgreement/ES/MEC/FPU14-06259
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2009-08389
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2015-69499-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2015-64486-R

Tipo y forma: Article (PrePrint)

Área (Departamento): Área Física Materia Condensada (Dpto. Física Materia Condensa.)