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Origin and Expansion of the Serine Protease Repertoire in the Myelomonocyte Lineage

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Origin and Expansion of the Serine Protease Repertoire in the Myelomonocyte Lineage International Journal of Molecular Sciences Review Origin and Expansion of the Serine Protease Repertoire in the Myelomonocyte Lineage Stefanie A. I. Weiss 1 , Salome R. T. Rehm 1, Natascha C. Perera 2, Martin L. Biniossek 3, Oliver Schilling 4,5 and Dieter E. Jenne 1,6,* 1 Comprehensive Pneumology Center (CPC-M), Institute of Lung Biology and Disease (iLBD) Helmholtz Zentrum München and University Hospital of the Ludwig-Maximilians University (LMU), 81377 Munich, Germany; [email protected] (S.A.I.W.); [email protected] (S.R.T.R.) 2 ARTTIC Innovation GmbH, 80333 Munich, Germany; [email protected] 3 Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; [email protected] 4 Institute of Surgical Pathology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; [email protected] 5 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany 6 Max Planck Institute of Neurobiology, 82152 Planegg-Martinsried, Germany * Correspondence: [email protected] Abstract: The deepest evolutionary branches of the trypsin/chymotrypsin family of serine proteases are represented by the digestive enzymes of the gastrointestinal tract and the multi-domain proteases of the blood coagulation and complement system. Similar to the very old digestive system, highly diverse cleavage specificities emerged in various cell lineages of the immune defense system during vertebrate evolution. The four neutrophil serine proteases (NSPs) expressed in the myelomonocyte lineage, neutrophil elastase, proteinase 3, cathepsin G, and neutrophil serine protease 4, collectively Citation: Weiss, S.A.I.; Rehm, S.R.T.; display a broad repertoire of (S1) specificities. The origin of NSPs can be traced back to a circulating Perera, N.C.; Biniossek, M.L.; liver-derived trypsin-like protease, the complement factor D ancestor, whose activity is tightly Schilling, O.; Jenne, D.E. Origin and controlled by substrate-induced activation and TNFα-induced locally upregulated protein secretion. Expansion of the Serine Protease However, the present-day descendants are produced and converted to mature enzymes in precursor Repertoire in the Myelomonocyte cells of the bone marrow and are safely sequestered in granules of circulating neutrophils. The Lineage. Int. J. Mol. Sci. 2021, 22, potential site and duration of action of these cell-associated serine proteases are tightly controlled 1658. https://doi.org/ by the recruitment and activation of neutrophils, by stimulus-dependent regulated secretion of the 10.3390/ijms22041658 granules, and by various soluble inhibitors in plasma, interstitial fluids, and in the inflammatory exudate. An extraordinary dynamic range and acceleration of immediate defense responses have Academic Editor: Lars Hellman Received: 31 December 2020 been achieved by exploiting the high structural plasticity of the trypsin fold. Accepted: 4 February 2021 Published: 7 February 2021 Keywords: serine proteases; trypsin ancestor; complement factor D; proteinase 3; cleavage specificity Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction: Distinction between an Ancient Trypsin and Chymotrypsin Cluster iations. Amide bonds in proteins are very slowly hydrolyzed by surrounding water molecules under natural conditions. However, this slow spontaneous hydrolysis reaction can be accelerated by proteinaceous catalysts, known as proteases, which improve the interaction of a specifically bound water molecule with an amide bond. In contrast to many other Copyright: © 2021 by the authors. posttranslational modifications such as protein phosphorylation, methylation, lipidation, Licensee MDPI, Basel, Switzerland. or oxidation, proteolysis cannot be proficiently reversed by religation of the respective This article is an open access article peptide fragments and is irreversible. Proteases are common and widespread enzymes and distributed under the terms and have been classified according to their catalytic mechanism of action as serine, cysteine, conditions of the Creative Commons metallo- and aspartyl-proteases. Serine-type proteases fall into three categories based on Attribution (CC BY) license (https:// their completely unrelated fold but share in each case the same geometry of the catalytic creativecommons.org/licenses/by/ serine and histidine residues [1]. 4.0/). Int. J. Mol. Sci. 2021, 22, 1658. https://doi.org/10.3390/ijms22041658 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 21 based on their completely unrelated fold but share in each case the same geometry of the catalytic serine and histidine residues [1]. Int. J. Mol. Sci. 2021, 22, 1658 In chymotrypsin/trypsin-like proteases, a third conserved aspartate 2residue, of 20 Asp102 (chymotrypsinogen numbering), complements the His57 and Ser195 residues and stabi- lizes the catalytic center of the enzyme (Figure 1). The amino acid residues of chymotryp- sin/trypsin-likeIn chymotrypsin/trypsin-like serine proteases proteases,are organize a thirdd conservedas two six-stranded aspartate residue, ß-barrels Asp102 which form two(chymotrypsinogen weakly homologous numbering), subdomains complements with the only His57 a and few Ser195 short residues helical and segments stabilizes on the sur- facethe [2]. catalytic The centerHis57 of and the enzyme Asp102 (Figure residues1). The aminoare located acid residues in the of chymotrypsin/trypsin-N-terminal and the Ser195 in like serine proteases are organized as two six-stranded ß-barrels which form two weakly thehomologous C-terminal subdomains ß-barrel. A with linker only aregion few short (residues helical segments 115 to 132 on the and surface the C-terminal [2]. The amphi- pathic,mainlyHis57 and Asp102 positively residues charged are located helix, in the connects N-terminal the and N- the and Ser195 C-terminal in the C-terminal ß-barrels. The side chainß-barrel. of the A substrate linker region residue (residues in the 115 P1 to position 132 and the, next C-terminal to the scissile amphipathic, peptide mainly bond, interacts withpositively the wall charged and the helix, bottom connects of thethe N- S1 and bind C-terminaling pocket. ß-barrels. Further The sideenzyme-substrate chain of the hydro- substrate residue in the P1 position, next to the scissile peptide bond, interacts with the genwall bonds and theat positions bottom of the P1 S1 and binding P3 and pocket. with Further the Gly193 enzyme-substrate residue of hydrogen the enzyme bonds help to po- sitionat positions the scissile P1 and peptide P3 and bond with thefor Gly193the attack residue by ofSer195. the enzyme help to position the scissile peptide bond for the attack by Ser195. Figure 1. Cα-main chain structure of a serine protease compared with its zymogen (light blue and Figureyellow 1. loops)Cα-main showing chain the structure N- and C-terminal of a serine ß-barrels protease (cyan) withcompared helices in with red. Theits zymogen residues of (light the blue and yellowcatalytic loops) triad showing (His, Asp, the and N- Ser) and are C-terminal shown as ball ß-barrels and stickmodels (cyan) and with map helices to the Nint (His,red. Asp)The residues of the andcatalytic Ct (Ser) triad ß-strand (His, barrel. Asp, After and removal Ser) are of show the N-terminaln as ball propeptide, and stick the models free N-terminus and map (N) to of the Nt (His, Asp)the and mature Ct (Ser) enzyme ß-strand (Ile16 to barrel. Gly19) inserts After into removal a pocket of of the the zymogenN-terminal and formspropeptide, a salt bridge the withfree N-terminus (N) Asp194of the (chymotrypsinogenmature enzyme (Ile16 numbering). to Gly19) Extensive insert reorientations into a pocket of three of surface the zymogen loops occurs and in theforms a salt t bridgeso-called with activation Asp194 domain(chymotrypsinogen (yellow loops) within numbering). the C-terminal Extensive ß-barrel reorientation (C ). The S1 pocket of three opens surface loops occurscompletely in the so-called and can now activation bind the P1 domain side chain (yellow of the substrate.loops) within The specificity the C-terminal of the S1 pocketß-barrel is (Ct). The S1 pocketdetermined opens bycompletely a few residues and of can the enzyme now bind directly the in P1 contact side with chain the of side the chain substrate. (adapted The from specificity [3]). of the S1 pocketThe is carbonyldetermined carbon by ofa fe thew amide residues bond of between the enzyme the P1 directly and P10 residuesin contact is attackedwith the by side chain (adaptedthe polarized from [3]). hydroxyl group of the Ser195. The N-terminal fragment of the substrate forms a transient covalent complex, while the C-terminal fragment of the substrate is released. A waterThe molecule carbonyl occupies carbon a position of the justamide vacated bond by the between N-terminal the P1 P10residue and ofP1 the′residues leaving is attacked by thefragment. polarized The latter hydroxyl hydrolyses group the of acyl-enzyme the Ser195 complex. The N-terminal and releases fragment the N-terminal of the substrate fragment with P1 at its C-terminus. In canonical inhibitor complexes, the reactive site formspeptide a transient bond remains covalent intact orcomplex, is slowlycleaved. while the By contrast, C-terminal suicide fragment inhibitors, i.e.,of the serpins, substrate is re- leased.form
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