Journal
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
Volume 71, Issue -, Pages 969-985Publisher
INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S1399004715002485
Keywords
integrin alpha 6 beta 4; FnIII-3; FnIII-4; small-angle X-ray scattering; double electron-electron resonance
Funding
- Spanish Ministry of Economy and Competitiveness
- European Regional Development Fund [BFU2009-08389, BFU2012-32847]
- SNF [200020_14441]
- Netherlands Science Foundation
- Dutch Cancer Society
- JAE contract (CSIC)
- Juan de la Cierva contract
- Ramon y Cajal contract
- University of Salamanca
- European Community's Seventh Framework Programme (FP7) under BioStruct-X [283570]
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Integrin alpha 6 beta 4 is a major component of hemidesmosomes that mediate the stable anchorage of epithelial cells to the underlying basement membrane. Integrin alpha 6 beta 4 has also been implicated in cell proliferation and migration and in carcinoma progression. The third and fourth fibronectin type III domains (FnIII-3,4) of integrin beta 4 mediate binding to the hemidesmosomal proteins BPAG1e and BPAG2, and participate in signalling. Here, it is demonstrated that X-ray crystallography, small-angle X-ray scattering and double electron-electron resonance (DEER) complement each other to solve the structure of the FnIII-3,4 region. The crystal structures of the individual FnIII-3 and FnIII-4 domains were solved and the relative arrangement of the FnIII domains was elucidated by combining DEER with site-directed spin labelling. Multiple structures of the interdomain linker were modelled by Monte Carlo methods complying with DEER constraints, and the final structures were selected against experimental scattering data. FnIII-3,4 has a compact and cambered flat structure with an evolutionary conserved surface that is likely to correspond to a protein-interaction site. Finally, this hybrid method is of general application for the study of other macromolecules and complexes.
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