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α2-Macroglobulins: Structure and Function

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Macromolecular Protein Complexes

Part of the book series: Subcellular Biochemistry ((SCBI,volume 83))

Abstract

α2-macroglobulins are broad-spectrum endopeptidase inhibitors, which have to date been characterised from metazoans (vertebrates and invertebrates) and Gram-negative bacteria. Their structural and biochemical properties reveal two related modes of action: the “Venus flytrap” and the “snap-trap” mechanisms. In both cases, peptidases trigger a massive conformational rearrangement of α2-macroglobulin after cutting in a highly flexible bait region, which results in their entrapment. In some homologs, a second action takes place that involves a highly reactive β-cysteinyl-γ-glutamyl thioester bond, which covalently binds cleaving peptidases and thus contributes to the further stabilization of the enzyme:inhibitor complex. Trapped peptidases are still active, but have restricted access to their substrates due to steric hindrance. In this way, the human α2-macroglobulin homolog regulates proteolysis in complex biological processes, such as nutrition, signalling, and tissue remodelling, but also defends the host organism against attacks by external toxins and other virulence factors during infection and envenomation. In parallel, it participates in several other biological functions by modifying the activity of cytokines and regulating hormones, growth factors, lipid factors and other proteins, which has a great impact on physiology. Likewise, bacterial α2-macroglobulins may participate in defence by protecting cell wall components from attacking peptidases, or in host-pathogen interactions through recognition of host peptidases and/or antimicrobial peptides. α2-macroglobulins are more widespread than initially thought and exert multifunctional roles in both eukaryotes and prokaryotes, therefore, their on-going study is essential.

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Acknowledgements

This study was funded in part by grants from European, Spanish, and Catalan agencies (FP7-PEOPLE-2011-ITN-290246 “RAPID”; FP7-HEALTH-2012-306029-2 “TRIGGER”; BFU2015-64487-R; BIO2013-49320-EXP; MDM-2014-0435; 2014SGR9). TG acknowledges “Juan de la Cierva” research contracts (JCI-2012-13573) from the Spanish Ministry for Economy and Competitiveness. The Structural Biology Unit of IBMB is a “María de Maeztu” Unit of Excellence of the Ministry of Economy and Competitiveness.

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  1. Proteolysis Lab, Structural Biology Unit, “María de Maeztu” Unit of Excellence, Molecular Biology Institute of Barcelona (CSIC), Barcelona Science Park; c/Baldiri Reixac, 15-21, 08028, Barcelona, Spain

    Irene Garcia-Ferrer, Aniebrys Marrero, F. Xavier Gomis-Rüth & Theodoros Goulas

  2. Present address: EMBL Grenoble, 71 Avenue des Martyrs; 38042 CS 90181, Grenoble Cedex 9, France

    Irene Garcia-Ferrer

  3. Present address: Department of Chemistry, University of Zürich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

    Aniebrys Marrero

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  1. Institute of Zoology, University of Mainz, Mainz, Germany

    J. Robin Harris

  2. School of Biology, Newcastle University, Newcastle upon Tyne, United Kingdom

    Jon Marles-Wright

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Garcia-Ferrer, I., Marrero, A., Gomis-Rüth, F.X., Goulas, T. (2017). α2-Macroglobulins: Structure and Function. In: Harris, J., Marles-Wright, J. (eds) Macromolecular Protein Complexes. Subcellular Biochemistry, vol 83. Springer, Cham. https://doi.org/10.1007/978-3-319-46503-6_6

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