PMID- 31995266
OWN - NLM
STAT- MEDLINE
DCOM- 20210517
LR  - 20210517
IS  - 1742-4658 (Electronic)
IS  - 1742-464X (Linking)
VI  - 287
IP  - 18
DP  - 2020 Sep
TI  - Human proteinase 3 resistance to inhibition extends to alpha-2 macroglobulin.
PG  - 4068-4081
LID - 10.1111/febs.15229 [doi]
AB  - Polymorphonuclear neutrophils contain at least four serine endopeptidases, namely 
      neutrophil elastase (NE), proteinase 3 (PR3), cathepsin G (CatG), and NSP4, which 
      contribute to the regulation of infection and of inflammatory processes. In 
      physiological conditions, endogenous inhibitors including alpha2-macroglobulin 
      (alpha2-M), serpins [alpha1-proteinase inhibitor (alpha1-PI)], monocyte neutrophil elastase 
      inhibitor (MNEI), alpha1-antichymotrypsin, and locally produced chelonianins (elafin, 
      SLPI) control excessive proteolytic activity of neutrophilic serine proteinases. 
      In contrast to human NE (hNE), hPR3 is weakly inhibited by alpha1-PI and MNEI but not 
      by SLPI. alpha2-M is a large spectrum inhibitor that traps a variety of proteinases 
      in response to cleavage(s) in its bait region. We report here that alpha2-M was more 
      rapidly processed by hNE than hPR3 or hCatG. This was confirmed by the 
      observation that the association between alpha2-M and hPR3 is governed by a k(ass) in 
      the </= 10(5)  m(-1) .s(-1) range. Since alpha2-M-trapped proteinases retain peptidase 
      activity, we first predicted the putative cleavage sites within the alpha2-M bait 
      region (residues 690-728) using kinetic and molecular modeling approaches. We 
      then identified by mass spectrum analysis the cleavage sites of hPR3 in a 
      synthetic peptide spanning the 39-residue bait region of alpha2-M (39pep-alpha2-M). Since 
      the 39pep-alpha2-M peptide and the corresponding bait area in the whole protein do 
      not contain sequences with a high probability of specific cleavage by hPR3 and 
      were indeed only slowly cleaved by hPR3, it can be concluded that alpha2-M is a poor 
      inhibitor of hPR3. The resistance of hPR3 to inhibition by endogenous inhibitors 
      explains at least in part its role in tissue injury during chronic inflammatory 
      diseases and its well-recognized function of major target autoantigen in 
      granulomatosis with polyangiitis.
CI  - (c) 2020 INSERM UMR. The FEBS Journal published by John Wiley & Sons Ltd on behalf 
      of Federation of European Biochemical Societies.
FAU - N'Guessan, Koffi
AU  - N'Guessan K
AD  - INSERM UMR-1100, CEPR "Centre d'Etude des Pathologies Respiratoires", Tours, 
      France.
AD  - Universite de Tours, France.
FAU - Grzywa, Renata
AU  - Grzywa R
AUID- ORCID: 0000-0002-4064-2409
AD  - Faculty of Chemistry, Department of Organic and Medicinal Chemistry, Wroclaw 
      University of Science and Technology, Poland.
FAU - Seren, Seda
AU  - Seren S
AD  - INSERM UMR-1100, CEPR "Centre d'Etude des Pathologies Respiratoires", Tours, 
      France.
AD  - Universite de Tours, France.
FAU - Gabant, Guillaume
AU  - Gabant G
AD  - Centre de Biophysique Moleculaire, UPR4301, CNRS, Affiliated with Universite 
      d'Orleans, Orleans, France.
FAU - Juliano, Maria A
AU  - Juliano MA
AD  - Departamento de Biofisica, Escola Paulista Medicina, Universidade Federal de Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Moniatte, Marc
AU  - Moniatte M
AD  - Proteomics Core Facility, Ecole Polytechnique Federale de Lausanne (EPFL), 
      Lausanne, Switzerland.
FAU - van Dorsselaer, Alain
AU  - van Dorsselaer A
AD  - LSMBO, CNRS UMR-7178 (CNRS-UdS), ECPM, Institut Pluridisciplinaire Hubert Curien, 
      Strasbourg, France.
FAU - Bieth, Joseph G
AU  - Bieth JG
AD  - Laboratoire d'Enzymologie, INSERM U392, Universite Louis Pasteur de Strasbourg, 
      Illkirch, France.
FAU - Kellenberger, Christine
AU  - Kellenberger C
AD  - Laboratoire de Chimie Bacterienne, UMR-7283, CNRS, Marseille, France.
FAU - Gauthier, Francis
AU  - Gauthier F
AD  - INSERM UMR-1100, CEPR "Centre d'Etude des Pathologies Respiratoires", Tours, 
      France.
AD  - Universite de Tours, France.
FAU - Wysocka, Magdalena
AU  - Wysocka M
AD  - Faculty of Chemistry, University of Gdansk, Gdansk, Poland.
FAU - Lesner, Adam
AU  - Lesner A
AUID- ORCID: 0000-0001-8335-3431
AD  - Faculty of Chemistry, University of Gdansk, Gdansk, Poland.
FAU - Sienczyk, Marcin
AU  - Sienczyk M
AUID- ORCID: 0000-0002-5528-5264
AD  - Faculty of Chemistry, Department of Organic and Medicinal Chemistry, Wroclaw 
      University of Science and Technology, Poland.
FAU - Cadene, Martine
AU  - Cadene M
AD  - Centre de Biophysique Moleculaire, UPR4301, CNRS, Affiliated with Universite 
      d'Orleans, Orleans, France.
FAU - Korkmaz, Brice
AU  - Korkmaz B
AUID- ORCID: 0000-0002-5159-8706
AD  - INSERM UMR-1100, CEPR "Centre d'Etude des Pathologies Respiratoires", Tours, 
      France.
AD  - Universite de Tours, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200224
PL  - England
TA  - FEBS J
JT  - The FEBS journal
JID - 101229646
RN  - 0 (Peptides)
RN  - 0 (Pregnancy-Associated alpha 2-Macroglobulins)
RN  - 0 (Recombinant Proteins)
RN  - EC 3.4.21.76 (Myeloblastin)
SB  - IM
MH  - Amino Acid Sequence
MH  - Binding Sites
MH  - Chromatography, Liquid/methods
MH  - Humans
MH  - Kinetics
MH  - Mass Spectrometry/methods
MH  - *Molecular Docking Simulation
MH  - Myeloblastin/*chemistry/genetics/metabolism
MH  - Peptides/chemistry/genetics/metabolism
MH  - Pregnancy-Associated alpha 2-Macroglobulins/*chemistry/genetics/metabolism
MH  - Protein Binding
MH  - Protein Domains
MH  - Proteolysis
MH  - Recombinant Proteins/*chemistry/metabolism
OTO - NOTNLM
OT  - proteinase 3
OT  - proteolysis
OT  - serine proteinase
OT  - alpha2-macroglobulin
EDAT- 2020/01/30 06:00
MHDA- 2021/05/18 06:00
CRDT- 2020/01/30 06:00
PHST- 2019/10/27 00:00 [received]
PHST- 2019/12/12 00:00 [revised]
PHST- 2020/01/27 00:00 [accepted]
PHST- 2020/01/30 06:00 [pubmed]
PHST- 2021/05/18 06:00 [medline]
PHST- 2020/01/30 06:00 [entrez]
AID - 10.1111/febs.15229 [doi]
PST - ppublish
SO  - FEBS J. 2020 Sep;287(18):4068-4081. doi: 10.1111/febs.15229. Epub 2020 Feb 24.