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Publication Detail
Two-domain structure of the native and reactive centre cleaved forms of C1 ̄ inhibitor of human complement by neutron scattering
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Perkins SJ, Smith KF, Amatayakul S, Ashford D, Rademacher TW, Dwek RA, Lachmann PJ, Harrison RA
  • Publication date:
  • Pagination:
    751, 763
  • Journal:
    Journal of Molecular Biology
  • Volume:
  • Issue:
  • Status:
  • Print ISSN:
The C1 ̄ inhibitor component of human complement is a member of the serpin superfamily, and controls C1 activation. Carbohydrate analyses showed that there are seven O-linked oligosaccharides in C1 ̄ inhibitor. Together with six N-linked complex-type oligosaccharides, the carbohydrate content is therefore 26% by weight and the molecular weight (Mr) is calculated as 71,100. Neutron scattering gives an Mr of 76,000 (± 4000) and a matchpoint of 41.8 to 42.3% 2H2O, in agreement with this carbohydrate and amino acid composition. Guinier plots to determine the radius of gyration RG were biphasic. Neutron contrast variation of C1 ̄ inhibitor in H2O-2H2O mixtures gave an overall radius of gyration RG at infinite contrast of 4.85 nm, from analyses at low Q, and a cross-sectional RG of 1.43 nm. The reactive centre cleaved form of C1 ̄ inhibitor has the same Mr and structure as the native molecule. The length of C1 ̄ inhibitor, 16 to 19 nm, is far greater than that of the putative serpin domain. This is attributed to an elongated structure for the carbohydrate-rich 113-residue N-terminal domain. The radial inhomogeneity of scattering density, α, is large at 59 × 10-5 from the RG data and 28 × 10-5 from the cross-sectional analysis, and this is accounted for by the high oligosaccharide content of C1 ̄ inhibitor. The scattering data were modelled using small spheres. A two-domain structure of length 18 nm based on two distinct scattering densities accounted for all the contrast variation data. One domain is based on the crystal structure of α1 antitrypsin (7 nm × 3 nm × 3 nm). The other corresponds to an extended heavily glycosylated N-terminal domain of length 15 nm, whose long axis is close to the longest axis of the serpin domain. Calculation of the sedimentation coefficient s20, w0 for CT inhibitor using the hydrodynamic sphere approach showed that a two-domain head and-tail structure with an Mr of 71,000 and longest axis of 16 to 19 nm successfully reproduced the s20, w0 of 3.7 S. Possible roles of the N-terminal domain in the function of C1 ̄ inhibitor are discussed. © 1990.
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