Iqbal, Hina;
Fung, Ka Wai;
Gor, Jayesh;
Bishop, Anthony C;
Makhatadze, George I;
Brodsky, Barbara;
Perkins, Stephen J;
(2023)
A solution structure analysis reveals a bent collagen triple helix in the complement activation recognition molecule mannan-binding lectin.
Journal of Biological Chemistry
, 299
(2)
, Article 102799. 10.1016/j.jbc.2022.102799.
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Abstract
Collagen triple helices are critical in the function of mannan-binding lectin (MBL), an oligomeric recognition molecule in complement activation. The MBL collagen regions form complexes with the serine proteases MASP-1 and MASP-2 in order to activate complement, and mutations lead to common immunodeficiencies. To evaluate their structure-function properties, we studied the solution structures of four MBL-like collagen peptides. The thermal stability of the MBL collagen region was much reduced by the presence of a GQG interruption in the typical (X-Y-Gly)n repeat compared to controls. Experimental solution structural data were collected using analytical ultracentrifugation and small angle X-ray and neutron scattering. As controls, we included two standard Pro-Hyp-Gly collagen peptides (POG)10-13, as well as three more peptides with diverse (X-Y-Gly)n sequences that represented other collagen features. These data were quantitatively compared with atomistic linear collagen models derived from crystal structures and 12,000 conformations obtained from molecular dynamics (MD) simulations. All four MBL peptides were bent to varying degrees up to 85o in the best-fit MD models. The best-fit benchmark peptides (POG)n were more linear but exhibited a degree of conformational flexibility. The remaining three peptides showed mostly linear solution structures. In conclusion, the collagen helix is not strictly linear, the degree of flexibility in the triple helix depends on its sequence, and the triple helix with the GQG interruption showed a pronounced bend. The bend in MBL GQG peptides resembles the bend in the collagen of complement C1q and may be key for lectin pathway activation.
| Type: | Article |
|---|---|
| Title: | A solution structure analysis reveals a bent collagen triple helix in the complement activation recognition molecule mannan-binding lectin |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jbc.2022.102799 |
| Publisher version: | https://doi.org/10.1016/j.jbc.2022.102799 |
| Language: | English |
| Additional information: | Copyright © 2022 The authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Analytical ultracentrifugation, atomistic modelling, collagen, complement, molecular dynamics, small angle neutron scattering, small angle X-ray scattering |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10162600 |
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