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Proteolysis, Complex Formation and Conformational Changes Drive the Complement Pathways

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Advancing Methods for Biomolecular Crystallography

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Abstract

The complement system is an important part of the mammalian immune defense in blood and interstitial fluids. This set of ~30 plasma proteins and receptors enables the host to recognize and clear invading pathogens and altered host cells, while protecting healthy host cells and tissues. Over the last 7 years, we have resolved the structural details of the central components of this system, which is referred to as the Alternative Pathway of complement activation, and deduced the molecular mechanisms that underlie the amplification and regulation of this protein network. In short, we revealed that large domain-domain rearrangements of these multi-domain proteins, upon proteolysis and complex formation, determine the specificity that provides a local and brief burst to mark targets cells for immune clearance. Most recently, we and others have revealed structural details of the Terminal Pathway that leads to pore formation by Membrane-Attack-Complexes in cell membranes yielding lysis.

This text is based on the research highlights of the Gros lab, see www.crystal.chem.uu.nl/~gros/researchhighlights.htm

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Acknowledgements

We gratefully acknowledge the help of many lab members and collaborators throughout the years and financial support from NWO-CW, NIH and ERC. Special thanks to Bert Janssen, Fin Milder, Jin Wu and Michael Hadders.

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Authors and Affiliations

  1. Crystal and Structural Chemistry, Bijvoet Center, Utrecht University, Utrecht, The Netherlands

    Piet Gros & Federico Forneris

Authors
  1. Piet Gros
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  2. Federico Forneris
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Corresponding author

Correspondence to Piet Gros .

Editor information

Editors and Affiliations

  1. , Department of Haematology, University of Cambridge, Hills Road, Cambridge, CB2 0XY, United Kingdom

    Randy Read

  2. Fac.des Sciences et des Technologies, Physics Department, Université de Lorraine, Blvd. des Aiguillettes 1, Vandoeuvre-lès-Nancy, 54506, France

    Alexandre G. Urzhumtsev

  3. , Institute of Mathematical Problems of Bi, Russian Academy of Sciences, Institutskaya st. 4, Pushchino, 142290, Russia

    Vladimir Y. Lunin

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Gros, P., Forneris, F. (2013). Proteolysis, Complex Formation and Conformational Changes Drive the Complement Pathways. In: Read, R., Urzhumtsev, A., Lunin, V. (eds) Advancing Methods for Biomolecular Crystallography. NATO Science for Peace and Security Series A: Chemistry and Biology. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6232-9_25

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