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Structural and functional insight into pan-endopeptidase inhibition by α2-macroglobulins

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Veröffentlicht/Copyright: 24. Juni 2017
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 398 Heft 9

Abstract

Peptidases must be exquisitely regulated to prevent erroneous cleavage and one control is provided by protein inhibitors. These are usually specific for particular peptidases or families and sterically block the active-site cleft of target enzymes using lock-and-key mechanisms. In contrast, members of the +1400-residue multi-domain α2-macroglobulin inhibitor family (α2Ms) are directed against a broad spectrum of endopeptidases of disparate specificities and catalytic types, and they inhibit their targets without disturbing their active sites. This is achieved by irreversible trap mechanisms resulting from large conformational rearrangement upon cleavage in a promiscuous bait region through the prey endopeptidase. After decades of research, high-resolution structural details of these mechanisms have begun to emerge for tetrameric and monomeric α2Ms, which use ‘Venus-flytrap’ and ‘snap-trap’ mechanisms, respectively. In the former, represented by archetypal human α2M, inhibition is exerted through physical entrapment in a large cage, in which preys are still active against small substrates and inhibitors that can enter the cage through several apertures. In the latter, represented by a bacterial α2M from Escherichia coli, covalent linkage and steric hindrance of the prey inhibit activity, but only against very large substrates.

Keywords: bait region cleavage; conformational rearrangement; irreversible inhibition; multi-domain protein; protein inhibitor; regulation of proteolytic activity

Acknowledgments

This study was supported in part by grants from European, Spanish, and Catalan agencies (grant references FP7-HEALTH-2012-306029-2 ‘TRIGGER’, BFU2015-64487R, MDM-2014-0435, BIO2013-49320-EXP, and 2014SGR9). The Structural Biology Unit (www.sbu.csic.es) of IBMB has been named a ‘María de Maeztu’ Unit of Excellence by the Spanish Ministry of Economy and Competitiveness. T.G. and I.G.-F. acknowledge a ‘Juan-de-la-Cierva’ contract from the Spanish Ministry of Economy and Competitiveness (JCI-2012-13573) and an FPU fellowship from the Spanish Ministry of Education and Culture (AP-2010-03799), respectively.

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Received: 2016-11-22
Accepted: 2017-2-18
Published Online: 2017-6-24
Published in Print: 2017-8-28

©2017 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. The role of sirtuins in mitochondrial function and doxorubicin-induced cardiac dysfunction
  4. Structural and functional insight into pan-endopeptidase inhibition by α2-macroglobulins
  5. Iron overload and altered iron metabolism in ovarian cancer
  6. Shared function and moonlighting proteins in molybdenum cofactor biosynthesis
  7. Minireview
  8. Molecular challenges imposed by MHC-I restricted long epitopes on T cell immunity
  9. Research Articles/Short Communications
  10. Protein Structure and Function
  11. The monoheme cytochrome c subunit of Alternative Complex III is a direct electron donor to caa3 oxygen reductase in Rhodothermus marinus
  12. Cell Biology and Signaling
  13. β-NGF and β-NGF receptor upregulation in blood and synovial fluid in osteoarthritis
https://doi.org/10.1515/hsz-2016-0329
Schlagwörter für diesen Artikel
bait region cleavage; conformational rearrangement; irreversible inhibition; multi-domain protein; protein inhibitor; regulation of proteolytic activity

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. The role of sirtuins in mitochondrial function and doxorubicin-induced cardiac dysfunction
  4. Structural and functional insight into pan-endopeptidase inhibition by α2-macroglobulins
  5. Iron overload and altered iron metabolism in ovarian cancer
  6. Shared function and moonlighting proteins in molybdenum cofactor biosynthesis
  7. Minireview
  8. Molecular challenges imposed by MHC-I restricted long epitopes on T cell immunity
  9. Research Articles/Short Communications
  10. Protein Structure and Function
  11. The monoheme cytochrome c subunit of Alternative Complex III is a direct electron donor to caa3 oxygen reductase in Rhodothermus marinus
  12. Cell Biology and Signaling
  13. β-NGF and β-NGF receptor upregulation in blood and synovial fluid in osteoarthritis
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