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Publication Detail
Conformational changes during the assembly of factor B from its domains by (1)H NMR spectroscopy and molecular modelling: their relevance to the regulation of factor B activity
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Hinshelwood J, Perkins SJ
  • Publication date:
  • Pagination:
    1267, 1285
  • Journal:
    Journal of Molecular Biology
  • Volume:
  • Issue:
  • Print ISSN:
  • Keywords:
    Allosteric Regulation, Amino Acid Sequence, Biochemistry, Biology, Catalytic Domain, chemistry, Complement 3, Complement Factor B, Complement Factor D, Crystallography, X-Ray, Electrostatics, Hydrogen, Hydrogen-Ion Concentration, interaction, isolation & purification, Magnetic Resonance Spectroscopy, metabolism, model, modelling, Models, Molecular, Molecular Biology, Molecular Sequence Data, N-terminal, NMR, peptide, Peptide Fragments, pH, Protein Structure, Tertiary, Sequence Alignment, Sequence Homology, Amino Acid, Serine, spectroscopy, Structure, Support, Non-U.S.Gov't, Temperature, Thermodynamics, von Willebrand Factor
  • Addresses:
    Department of Biochemistry and Molecular Biology, Royal Free Campus, Royal Free and University College Medical School, University College London, Rowland Hill Street, London, NW3 2PF, UK
  • Notes:
    UI - 20425116 LA - eng RN - 0 (Complement 3) RN - 0 (Peptide Fragments) RN - 0 (von Willebrand Factor) RN - 1333-74-0 (Hydrogen) RN - EC (Complement Factor D) RN - EC (Complement Factor B) PT - Journal Article DA - 20000922 IS - 0022-2836 SB - IM CY - ENGLAND JC - J6V
Factor B is a key component of the alternative pathway of complement and is cleaved by factor D into the Ba and Bb fragments in the presence of activated C3 (C3b or C3(H(2)O)). The Ba fragment contains three short consensus/complement repeat domains, while the Bb fragment contains a von Willebrand factor type A (vWF-A) domain and a serine protease (SP) domain, all three of which are implicated in multisite contacts with C3. The upfield-shifted signals in the (1)H NMR spectra of factor B, the Ba and Bb fragments, and the vWF-A and SP domains were used as sensitive conformational probes of their structures. Temperature studies and pH titrations showed that the Ba fragment and the vWF-A and SP domains had conformationally mobile structures. The comparison of the NMR spectra of the SP domains of both factor B and factor D showed that the factor D linewidths were broader than those for factor B, which may result from a range of proteolytically inactive conformations of factor D in the absence of substrate. The NMR spectra from the separate vWF-A and SP domains in combination with that of the Ba fragment generally accounted for that of intact factor B, apart from the perturbation of an upfield-shifted signal from the Ba fragment. A new upfield-shifted signal was observed in the Bb fragment that was not detected in the spectra for the vWF-A or SP domains or intact factor B. Ring current calculations based on homology models or crystal structures predicted that buried hydrophobic methyl-aromatic interactions probably accounted for the upfield-shifted signals, with many arising from the N-terminal subdomain of the SP domain to which the C terminus of the vWF-A domain is directly linked. It was concluded that: (1) the conformation of the free SP domain is better ordered in solution than that of factor D; (2) the conformation of the Ba fragment is affected by its incorporation into factor B; and (3) the proximity of the vWF-A and SP domains within the Bb fragment leads to a conformational change in which conserved charged residues may be important. Allosteric structural rearrangements in the SP domain as the result of its interactions with the vWF-A domain or the Ba fragment provide an explanation of the regulation of the catalytic activity of factor B
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