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Post-Translational Modifications of Circulating Alpha-1-Antitrypsin Protein

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Post-Translational Modifications of Circulating Alpha-1-Antitrypsin Protein International Journal of Molecular Sciences Review Post-Translational Modifications of Circulating Alpha-1-Antitrypsin Protein Urszula Lechowicz 1 , Stefan Rudzinski 1, Aleksandra Jezela-Stanek 1 , Sabina Janciauskiene 1,2 and Joanna Chorostowska-Wynimko 1,* 1 Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland; [email protected] (U.L.); [email protected] (S.R.); [email protected] (A.J.-S.); [email protected] (S.J.) 2 Member of the German Center for Lung Research DZL, Department of Respiratory Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover BREATH, 30625 Hannover, Germany * Correspondence: [email protected]; Tel.: +48-224312158 Received: 9 November 2020; Accepted: 30 November 2020; Published: 2 December 2020 Abstract: Alpha-1-antitrypsin (AAT), an acute-phase protein encoded by the SERPINA1 gene, is a member of the serine protease inhibitor (SERPIN) superfamily. Its primary function is to protect tissues from enzymes released during inflammation, such as neutrophil elastase and proteinase 3. In addition to its antiprotease activity, AAT interacts with numerous other substances and has various functions, mainly arising from the conformational flexibility of normal variants of AAT. Therefore, AAT has diverse biological functions and plays a role in various pathophysiological processes. This review discusses major molecular forms of AAT, including complex, cleaved, glycosylated, oxidized, and S-nitrosylated forms, in terms of their origin and function. Keywords: alpha-1-antitrypsin; AAT; SERPINA1; chronic obstructive pulmonary disease; protease inhibitor; S-nitrosylation; glycosylation; oxidation; carbamylation; homocysteinylation 1. Introduction The amino acid sequence determines the three-dimensional structure of each protein, although each protein’s function is largely modulated by post-translational modifications (PTMs). The term PTM indicates changes in the polypeptide chain because of the addition or removal of distinct chemical moieties to amino acid residues, proteolytic processing of the protein, or interactions between the protein and other substances [1,2]. Protein PTMs are involved in most cellular processes including metabolic regulation and defense against pathological insults. Therefore, recognition and analyses of protein PTMs, as well as efforts to understand their biological significance, are fundamental considerations in experimental and clinical science. Because PTMs are implicated in the development of various diseases, there are increasing efforts to identify connections between altered PTMs and the development of specific pathologies. Alpha-1-antitrypsin (AAT) is the prototypical member of the serine protease inhibitor (SERPIN) superfamily (Figure1)[ 3]. The AAT coding gene, SERPINA1, is 12.2 kb in length and composed of seven exons (Ia, Ib, Ic, and II–V) and six introns. It resides in a gene cluster that includes α1-antichymotrypsin, AAT pseudogene, cortisol-binding globulin, and protein C inhibitor [4]. SERPINA1 is extremely polymorphic, such that more than 150 single-nucleotide polymorphisms have been reported. The SERPINA1 pathogenic variants are known to cause AAT deficiency (AATD), an autosomal-codominant disorder. There are several clinically relevant genetic variants of the AAT protein with low expression levels, which polymerize spontaneously or show minimal/no inhibitory Int. J. Mol. Sci. 2020, 21, 9187; doi:10.3390/ijms21239187 www.mdpi.com/journal/ijms Int. J. Mol. Sci. Sci. 20202020,, 2211,, x 9187 FOR PEER REVIEW 212 of 1821 permits the generation of various molecular forms (e.g., polymeric, cleaved, oxidized, and complexed activitywithInt. J. Mol.other [ 5Sci.,6]. 20substances Normal20, 21, x FOR variants) PEER[7,8] REVIEW of. AATAccordingly also possess, AAT considerable demonstrates conformational broad biological flexibility activity that permits21 andof 21 theparticipates generation in various of various pathophysiological molecular forms processes. (e.g., polymeric, cleaved, oxidized, and complexed with permits the generation of various molecular forms (e.g., polymeric, cleaved, oxidized, and complexed otherThis substances) review [discusses7,8]. Accordingly, some of AATthe most demonstrates common broadtypes biologicalof PTMs activitycurrently and studied participates in AAT in with other substances) [7,8]. Accordingly, AAT demonstrates broad biological activity and variousresearch, pathophysiological focusing on their origin processes. and functionality (Figure 2). participates in various pathophysiological processes. This review discusses some of the most common types of PTMs currently studied in AAT research, focusing on their origin and functionality (Figure 2). Figure 1. SchematicSchematic structure structure of of native native alpha alpha-1-antitrypsin.-1-antitrypsin. The The reactive reactive center center loop loop (RCL), (RCL), three three β- β-sheets, and nine α-helices are depicted. The amino acids discussed in the text are marked in the sheets, and nine α-helices are depicted. The amino acids discussed in the text are marked in the diagram as Asn46, Asn83, and Asn247 (surrounded by circles)circles) are glycosylationglycosylation sites; Met351 and Figure 1. Schematic structure of native alpha-1-antitrypsin. The reactive center loop (RCL), three β- Met358 are residues that undergo oxidation; Cys232 is an S-nitrosylationS-nitrosylation site; and Glu342 is the site sheets, and nine α-helices are depicted. The amino acids discussed in the text are marked in the of Glu342Lys substitution. substitution. The The alpha alpha-1-antitrypsin-1-antitrypsin (AAT (AAT)) native native diagram diagram was was prepared prepared based based on data on diagram as Asn46, Asn83, and Asn247 (surrounded by circles) are glycosylation sites; Met351 and dataobtained obtained from from thethe SWISS SWISS-MODEL-MODEL repository repository ( https://swissmodel.expasy.orghttps://swissmodel.expasy.org lastlast accessed accessed on on 23 Met358 are residues that undergo oxidation; Cys232 is an S-nitrosylation site; and Glu342 is the site November23.11.2020). 2020). of Glu342Lys substitution. The alpha-1-antitrypsin (AAT) native diagram was prepared based on data Thisobtained review from discusses the SWISS some-MODEL of the most repository common (https://swissmodel.expasy.org types of PTMs currently studied last accessed in AAT research,on focusing23.11.2020 on their). origin and functionality (Figure2). Figure 2. The array of AAT roles: links between molecular form and function. Diagram created based on data from a previous study [9]. Figure 2. The array of AAT roles: links between molecular form and function. Diagram created based 2. GlycosylationFigure 2. The arrayof AAT of AAT roles: links between molecular form and function. Diagram created based on data fromfrom aa previousprevious studystudy [[9]9].. Protein glycosylation encompasses a diverse array of sugar-moiety additions to proteins and is 2. Glycosylation of AAT a2. major Glycosylation type of PTM of AAT with important effects on protein folding, conformation, distribution, stability, and activity.Protein glycosylationCarbohydrates encompasses in the form aof diverse asparagine array (Asn) of sugar-moiety-linked (N-linked) additions or serine/threonine to proteins and- Protein glycosylation encompasses a diverse array of sugar-moiety additions to proteins and is islinked a major (O-linked) type of oligosaccharides PTM with important are major effects structural on protein components folding, conformation,of many secreted distribution, proteins a major type of PTM with important effects on protein folding, conformation, distribution, stability, stability,[10,11]. Human and activity. AAT is a glycoprotein Carbohydrates with in a thecarbohydrate form of asparaginecontent of approximately (Asn)-linked 15% (N-linked) [12]. AAT or and activity. Carbohydrates in the form of asparagine (Asn)-linked (N-linked) or serine/threonine- serinedemonstrates/threonine-linked Asn-linked (O-linked) glycosylation oligosaccharides at three specific are major sites structural on its polypeptide components backbone of many. secretedTwo of linked (O-linked) oligosaccharides are major structural components of many secreted proteins proteinsthese sites [10 are,11 ].present Human on AAT Asn is 46 a and glycoprotein Asn 83, encoded with a carbohydrate within exon content II, and ofone approximately site is located 15% on Asn [12]. [10,11]. Human AAT is a glycoprotein with a carbohydrate content of approximately 15% [12]. AAT AAT247, encoded demonstrates within Asn-linked exon III glycosylation[13]. Core glycans at three N specific-acetylglucosamine sites on its polypeptide are directly backbone. attached Twoto the of demonstrates Asn-linked glycosylation at three specific sites on its polypeptide backbone. Two of theseprotein sites via are Asn present residues on. Asn Subsequently 46 and Asn added 83, encoded glycans within include exon galactose, II, and one mannose, site is located fucose, on and Asn sialic 247, these sites are present on Asn 46 and Asn 83, encoded within exon II, and one site is located on Asn acid, which form bi-, tri-, and tetra-antennary branching structures. There are nine known glycoforms 247, encoded within exon III [13]. Core glycans N-acetylglucosamine are directly attached to the protein via Asn residues. Subsequently added glycans include galactose, mannose, fucose, and sialic acid, which form bi-, tri-, and tetra-antennary
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