Affinage

SERPINA1

Alpha-1-antitrypsin · UniProt P01009

Round 2 corrected
Length
418 aa
Mass
46.7 kDa
Annotated
2026-04-28
130 papers in source corpus 37 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SERPINA1 encodes alpha-1-antitrypsin (A1AT), a secreted serpin-family serine protease inhibitor that functions as the principal physiological inhibitor of neutrophil elastase and serves broader roles in immune regulation and metabolic homeostasis. A1AT employs a suicide-inhibitor mechanism in which its reactive center loop, with Met358 as the protease 'bait', is cleaved by the target protease, triggering a 71 Å translocation of the loop that carries the covalently tethered protease to the opposite pole of the molecule, distorting its active site and preventing release (PMID:11057674, PMID:6332197). Beyond elastase inhibition, A1AT directly binds IL-8 to block CXCR1-mediated neutrophil chemotaxis, inhibits ADAM-17 to preserve Fcγ RIIIb on neutrophil membranes (PMID:21060150), inhibits proteinase 3 to protect anti-inflammatory IL-32γ in the liver (PMID:39939782), and acts as a hepatokine that complexes with EphB2 to promote adipocyte UCP1 expression and energy metabolism (PMID:39532838). The Z variant (Glu342Lys) disrupts a critical salt bridge, causing ER retention, polymerization via Hrd1/SEL1L/OS-9/GRP94-dependent ERAD, hepatocyte inclusion body disease, and reduced circulating A1AT predisposing to emphysema (PMID:18264092, PMID:6093867, PMID:12464660).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1982 High

    Establishing A1AT as the primary tissue scavenger of leukocyte elastase and linking the common S and Z deficiency variants to emphysema pathogenesis answered the fundamental question of what protease–antiprotease imbalance drives lung destruction.

    Evidence Protein sequence determination and variant analysis in human plasma

    PMID:7045697

    Open questions at the time
    • Mechanism of inhibition unknown at atomic level
    • Molecular basis of Z and S variant dysfunction not yet resolved
  2. 1983 High

    The Pittsburgh variant (Met358→Arg) demonstrated that reactive center identity dictates protease specificity, converting A1AT from an elastase inhibitor to a thrombin inhibitor and establishing the bait-residue paradigm for the entire serpin family.

    Evidence Characterization of a naturally occurring active-site mutation in a patient with fatal bleeding disorder

    PMID:6604220

    Open questions at the time
    • How the conformational change upon cleavage traps the protease was structurally undefined
  3. 1984 High

    Determination of the crystal structure of cleaved A1AT and the complete gene/cDNA sequence revealed the three β-sheet / eight α-helix architecture, placed Glu342 at a strategic position for the conformational rearrangement (explaining Z-variant pathology), and defined the S-variant as Glu264→Val.

    Evidence X-ray crystallography at 3 Å (two crystal forms) and cDNA/gene sequencing

    PMID:6093867 PMID:6332197

    Open questions at the time
    • Native (uncleaved) structure not yet solved
    • Atomic mechanism of loop translocation unknown
  4. 1996 High

    The native-form crystal structure at 2.9 Å showed the reactive center loop in a canonical β-strand conformation without insertion into the molecule, supporting a two-stage inhibition mechanism and providing a structural basis for aberrant polymerization.

    Evidence X-ray crystallography at 2.9 Å resolution

    PMID:8756325

    Open questions at the time
    • Full serpin–protease complex structure not yet available
    • Polymer interface not resolved atomically
  5. 2000 High

    Three simultaneous advances resolved core mechanism: (1) the serpin–protease complex crystal structure showed the 71 Å loop translocation drags and distorts the tethered protease; (2) mutagenesis/MS established that oxidation of either Met351 or Met358 abolishes elastase inhibition; (3) chemical chaperone PBA rescued Z-A1AT secretion in cells and PiZ mice.

    Evidence Crystal structure of serpin–protease complex; site-directed mutagenesis with mass spectrometry and elastase assays; PBA treatment in cell culture and PiZ transgenic mice

    PMID:10677536 PMID:10867014 PMID:11057674

    Open questions at the time
    • In vivo relevance of oxidative inactivation at physiological oxidant concentrations not fully tested
    • Whether PBA corrects polymerization or simply accelerates folding kinetics unresolved
  6. 2003 High

    Identification of a druggable hydrophobic cavity on β-sheet A (Thr114, Gly117) that, when filled by mutagenesis, stabilized the molecule and retarded polymerization without affecting inhibitory activity, provided the first structure-based target for anti-polymerization small molecules.

    Evidence Site-directed mutagenesis with thermal stability, polymerization kinetics, and Xenopus oocyte secretion assays

    PMID:12807889

    Open questions at the time
    • No small-molecule ligand for the cavity identified
    • Effect on Z-variant polymerization in hepatocytes not tested
  7. 2008 High

    Mapping Z-A1AT degradation onto the Hrd1/SEL1L/OS-9/GRP94 ERAD pathway answered how misfolded Z-A1AT is targeted for proteasomal destruction in the ER, explaining the gain-of-toxic-function hepatic disease.

    Evidence Co-immunoprecipitation and RNAi knockdown of ERAD components with Z-A1AT degradation assays in mammalian cells

    PMID:18264092

    Open questions at the time
    • Contribution of autophagy vs. ERAD to Z-polymer clearance not fully delineated
    • Whether ERAD saturation triggers the inflammatory hepatic response is unclear
  8. 2009 High

    Discovery that A1AT is internalized by lung endothelial cells via clathrin-mediated endocytosis—and that cigarette smoke inhibits this uptake—established that delivery of circulating A1AT to the lung interstitium requires active receptor-mediated transcytosis rather than passive diffusion.

    Evidence Pharmacological endocytic pathway inhibition, co-IP with clathrin heavy chain, in vivo mouse cigarette smoke exposure

    PMID:19423638

    Open questions at the time
    • Receptor identity for clathrin-dependent uptake not identified at this stage
  9. 2010 High

    Demonstration that A1AT directly binds IL-8 to block CXCR1 signaling and independently inhibits ADAM-17 to maintain Fcγ RIIIb on neutrophils revealed two protease-independent anti-inflammatory pathways, extending A1AT's function beyond elastase inhibition.

    Evidence Direct binding assays, ADAM-17 enzymatic inhibition, flow cytometry for Fcγ RIIIb; human AAT-deficient patient samples with augmentation therapy

    PMID:21060150

    Open questions at the time
    • Structural basis of A1AT–IL-8 interaction unresolved
    • Whether ADAM-17 inhibition is direct active-site engagement or allosteric unclear
  10. 2015 High

    Identification of SR-BI as an endothelial receptor for A1AT uptake, confirmed by knockout mouse phenotype, resolved the receptor question for pulmonary transcytosis and linked A1AT biology to lipoprotein receptor pathways.

    Evidence Co-IP, siRNA knockdown, competitive ligand blocking, Scarb1 KO mice, immunogold EM

    PMID:26092999

    Open questions at the time
    • Whether SR-BI is the sole receptor or acts redundantly with other receptors not resolved
    • Caveolae vs. clathrin contribution to SR-BI-mediated uptake not fully dissected
  11. 2016 High

    NQO1 was identified as an RNA-binding protein that binds the SERPINA1 3′-UTR and coding region to enhance A1AT translation, revealing a post-transcriptional regulatory axis confirmed by NQO1-KO mice having reduced serum A1AT and increased elastase activity.

    Evidence RNP immunoprecipitation, biotin pulldown, polysome profiling, luciferase reporters, NQO1-KO mice

    PMID:27515817

    Open questions at the time
    • How NQO1's oxidoreductase activity relates to its RNA-binding function unknown
    • Other trans-acting factors regulating SERPINA1 mRNA not characterized
  12. 2022 High

    Systematic SHAPE probing and mutagenesis of the SERPINA1 5′-UTR revealed a structured RNA domain that optimizes cap-dependent translation by maintaining accessibility at the initiation site, adding a cis-regulatory layer to A1AT translational control.

    Evidence SHAPE structure probing, systematic 5′-UTR mutagenesis, cap-dependent translation reporter assays

    PMID:36107773

    Open questions at the time
    • In vivo relevance of 5′-UTR structure under stress conditions not tested
    • Whether disease-associated variants affect 5′-UTR folding unknown
  13. 2024 High

    A1AT was shown to function as a hepatokine that complexes with EphB2 to induce adipocyte UCP1 expression and preadipocyte proliferation, establishing an endocrine role in energy metabolism beyond its canonical antiprotease function.

    Evidence Co-IP of A1AT–EphB2 complex; liver-specific transgenic and KO mice with metabolic phenotyping; in vitro adipocyte assays

    PMID:39532838

    Open questions at the time
    • Stoichiometry and structural basis of A1AT–EphB2 complex unknown
    • Whether this function requires serpin inhibitory activity is untested
  14. 2025 High

    Identification of the PR3/IL-32γ axis as a hepatic target of A1AT in MASH revealed that Kupffer cell IL-1β suppresses A1AT expression via HNF4α, enabling PR3 to cleave protective IL-32γ, which links A1AT deficiency to steatohepatitis progression.

    Evidence Quintuple Serpina1a-e KO mice, fast-food diet MASH model, PR3-resistant IL-32γ mutant, A1AT restoration experiments

    PMID:39939782

    Open questions at the time
    • Relevance to human MASH with normal A1AT genotype not established
    • Whether PR3 inhibition fully recapitulates A1AT restoration unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the atomic structure of A1AT polymers; the structural basis of the A1AT–IL-8 and A1AT–EphB2 interactions; the mechanism by which NQO1's RNA-binding and oxidoreductase activities are coordinated; and whether A1AT's metabolic hepatokine function is serpin-activity dependent or represents an entirely independent molecular surface.
  • Polymer interface not resolved at atomic level despite decades of effort
  • No crystal structure of A1AT–EphB2 or A1AT–IL-8 complex
  • Therapeutic targeting of the β-sheet A cavity not validated in human trials

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 3 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 7 GO:0005783 endoplasmic reticulum 4 GO:0031410 cytoplasmic vesicle 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-1430728 Metabolism 1
Partners
ADAM17CLTCCXCL8ELANEEPHB2NQO1PRTN3SCARB1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 Crystal structure of alpha-1-antitrypsin (cleaved form) determined at 3 Å resolution, revealing the polypeptide arranged into three beta-sheets (A, B, C) and eight alpha-helices. The structure showed that Met358 and Ser359 chain ends are on opposite poles of the molecule, indicating a major conformational rearrangement upon cleavage of the reactive center loop. Glu342, mutated to Lys in the Z-variant, was identified in a strategic position for this rearrangement. X-ray crystallography (isomorphous replacement, cyclic averaging of two crystal forms, crystallographic refinement to R~0.25) Journal of molecular biology High 6332197
1982 Primary sequence analysis of alpha-1-antitrypsin established its role as a tissue scavenger of leukocyte elastase and showed that two abnormal variants (S and Z) common in Europeans cause deficiency predisposing to emphysema. Cigarette smoking was shown to greatly accelerate the degenerative process by inactivating the reactive center. Protein sequence determination and variant analysis Nature High 7045697
1983 Mutation of the active-site Met358 to Arg in the Pittsburgh variant converted alpha-1-antitrypsin from an elastase inhibitor to a thrombin inhibitor (antithrombin activity), establishing Met358 as the reactive center that acts as 'bait' for neutrophil elastase, analogous to Arg393 in antithrombin III acting as bait for thrombin. This confirmed that reactive center identity determines protease specificity. Characterization of a naturally occurring Met358Arg mutation in a patient with fatal bleeding disorder; plasma protein analysis The New England journal of medicine High 6604220
1984 Complete cDNA and gene sequence of alpha-1-antitrypsin determined, revealing a 24-amino acid signal peptide and 394-amino acid mature protein. The S-variant gene was sequenced, identifying a single base substitution (A→T) causing Glu264→Val substitution. The gene structure includes four coding exons and a 5.3 kb intron in the 5' noncoding region. cDNA cloning and sequencing; gene subcloning and sequencing Biochemistry High 6093867
1988 Comprehensive molecular characterization of A1AT established: (1) the protein is a 52-kDa, 394-amino acid globular molecule with nine alpha-helices and three beta-pleated sheets; (2) the active site is centered around Met358 in an external stressed reactive center loop; (3) two critical salt bridges (Glu342-Lys290; Glu263-Lys387) exist within the molecule, and disruption of either causes distinct molecular pathology reducing serum A1AT levels; (4) over 75 variants exist categorized as normal, deficient, dysfunctional, or absent. Protein structural analysis, molecular biology, restriction fragment analysis, oligonucleotide probing, direct gene sequencing The American journal of medicine High 3289385
1996 Crystal structure of alpha-1-antitrypsin at 2.9 Å resolution showed the reactive site loop in a stable canonical beta-pleated strand conformation matching that found in all other serine proteinase inhibitor families (Kunitz, Kazal), without loop insertion into the body of the molecule. This favors a two-stage mechanism of inhibition and provides a structural basis for serpin polymerization in disease and for association with beta-amyloid. X-ray crystallography at 2.9 Å resolution Nature structural biology High 8756325
2000 Crystal structure of a serpin-protease complex revealed the complete mechanism of inhibition: the conformational change is initiated by reaction of the protease's active serine with the serpin reactive center, cleaving it. The cleaved reactive center loop then translocates 71 Å to the opposite pole of the serpin, dragging the tethered protease with it. This causes 37% loss of structure in the protease through distortion of its active site (plucking of the serine from its catalytic triad), preventing release of the protease from the complex and allowing its proteolytic destruction. X-ray crystallography of serpin-protease complex Nature High 11057674
2000 Oxidation of either Met351 or Met358 in alpha-1-antitrypsin causes loss of anti-neutrophil elastase activity. Both methionines are equally susceptible to hydrogen peroxide oxidation (confirmed by mass spectrometry). Single mutants M351V and M358V showed partial resistance to oxidative inactivation, while the double mutant M351V/M358V was markedly resistant, establishing that oxidation of either residue can inactivate A1AT and providing a mechanism for regulation of A1AT activity at sites of inflammation (e.g., by cigarette smoke). Site-directed mutagenesis of recombinant A1AT; hydrogen peroxide treatment; mass spectrometry for oxidation site identification; elastase inhibition assay The Journal of biological chemistry High 10867014
2000 Chemical chaperones, particularly 4-phenylbutyric acid (PBA), mediate increased secretion of functionally active mutant Z alpha-1-antitrypsin (alpha1-ATZ) from the ER. Oral administration of PBA to PiZ transgenic mice increased blood levels of human alpha-1-AT to 20-50% of normal levels, demonstrating that pharmacological intervention in ER retention of misfolded Z-A1AT is possible. Cell culture model (secretion assay); in vivo oral administration to PiZ transgenic mice; functional activity assessment Proceedings of the National Academy of Sciences of the United States of America High 10677536
1990 Neutrophil collagenase (MMP-8) is capable of cleaving and inactivating alpha-1-antitrypsin. Purified collagenase cleaved A1AT at almost twice the rate at which it cleaved type I collagen. Neutrophil gelatinase also cleaved A1AT but slowly. This was demonstrated by co-fractionation of collagenase and A1AT-cleaving activities by SDS-PAGE and confirmed with purified collagenase preparations, establishing metalloproteinase-mediated inactivation of the primary neutrophil elastase inhibitor. Preparative SDS-PAGE fractionation of neutrophil supernatant; incubation with purified substrates; Western blot; purified collagenase activity assay; inhibitor studies with 1,10-phenanthroline The Biochemical journal High 2173552
1990 Prostate-specific antigen (PSA) forms stable SDS-stable complexes with alpha-1-antichymotrypsin (but also interacts with alpha-2-macroglobulin) when added to normal blood plasma in vitro. PSA cleaves the inhibitor at a position identical to that reported for chymotrypsin-alpha-1-antichymotrypsin reaction, demonstrating that A1AT-family serpins can form covalent inhibitory complexes with serine proteases via standard serpin mechanism. In vitro complex formation with purified proteins; SDS-PAGE; plasma incubation experiments European journal of biochemistry Medium 1702714
1994 Alveolar epithelial cells (human A549 cell line and rat type-II pneumocytes) synthesize and secrete alpha-1-antitrypsin with modified glycosylation compared to serum AAT. The secreted A1AT retains the ability to form complexes with neutrophil elastase, establishing alveolar epithelial cells as a local source of A1AT for antiprotease defense within the lung. Northern blot for mRNA; immunoreactive AAT measurement by ELISA; complex formation assay with neutrophil elastase FEBS letters Medium 8013628
1996 Neutrophils store alpha-1-antitrypsin intracellularly and release it concordantly with neutrophil elastase (NE) upon surface stimulation. Flow cytometry showed decreased intracellular A1AT after stimulation with cytochalasin B/fMLP. Radiolabeling and immunoprecipitation demonstrated increased secretion of A1AT from stimulated neutrophils, with some secreted A1AT forming complexes with NE. This establishes an intrinsic mechanism by which neutrophils dampen the local effects of their own most powerful proteolytic enzyme. Immunofluorescence; quantitative flow cytometry; [35S]methionine labeling and immunoprecipitation; surface stimulation with cytochalasin B/fMLP American journal of respiratory and critical care medicine Medium 8970377
2002 Alpha-1-antitrypsin deficiency and the serpinopathies are characterized by pathological polymerization of mutant A1AT (Z variant, Glu342Lys) within the ER of hepatocytes, forming ordered polymers that cause liver disease while reduced circulating A1AT causes lung disease. The Z mutation disrupts the critical Glu342-Lys290 salt bridge, destabilizing the molecule and promoting polymer formation via aberrant beta-sheet interactions. Review synthesizing structural, cell biological, and molecular genetic data on serpin polymerization The Journal of clinical investigation Medium 12464660
2003 A hydrophobic surface cavity in alpha-1-antitrypsin on strand 2 of beta-sheet A (around residues Thr114, Gly117, Leu100) was identified as a target for preventing polymer formation. Mutations Thr114→Phe and Gly117→Phe significantly raised the melting temperature and retarded polymer formation without affecting inhibitory activity, while Leu100→Phe accelerated polymerization. Thr114→Phe reduced polymer formation and increased secretion of Z-A1AT from Xenopus oocytes. Cysteine mutants in the cavity could bind fluorophores, confirming accessibility. Site-directed mutagenesis; thermal stability assay; polymerization assay; Xenopus oocyte expression system; fluorophore binding to cysteine mutants The Journal of biological chemistry High 12807889
2006 Serpina1 (alpha-1-antitrypsin) acts as a potent inhibitor of IL-8-induced hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization. After low-dose total-body irradiation (0.5 Gy), Serpina1 mRNA and protein increased in bone marrow extracellular extracts. Antibody neutralization of Serpina1 reversed inhibitory activity. Exogenous Serpina1 administration almost completely inhibited HSC/HPC mobilization, while heat-inactivated Serpina1 had no effect, demonstrating that elastase-inhibitory activity is required for this function. In vivo mouse model; bone marrow extract biochemistry; anti-Serpina1 antibody neutralization; exogenous protein administration; heat inactivation control Proceedings of the National Academy of Sciences of the United States of America High 16432201
2008 OS-9 (an ER-resident lectin) and GRP94 (ER chaperone) deliver mutant alpha-1-antitrypsin (Z variant) to the Hrd1-SEL1L ubiquitin ligase complex for ER-associated degradation (ERAD). OS-9 binds ERAD substrates and, through the SEL1L adaptor, connects to Hrd1. GRP94, together with Hrd1 and SEL1L, is required for degradation of mutant alpha-1-antitrypsin, placing Z-A1AT degradation in a defined ERAD pathway. Co-immunoprecipitation; RNAi knockdown; protein degradation assays in mammalian cells Nature cell biology High 18264092
2009 Alpha-1-antitrypsin is internalized by primary rat lung microvascular endothelial cells via clathrin-mediated (not caveolae-mediated) endocytosis. A1AT associates with clathrin heavy chains but not caveolin-1 at the plasma membrane. Inhibition of clathrin-mediated endocytosis profoundly decreased A1AT internalization and reversed its antiapoptotic action. Cigarette smoke exposure significantly inhibited A1AT uptake in endothelial cells and in mouse lung in vivo, and altered intracellular distribution of clathrin heavy chains. Specific pharmacological inhibition of endocytic pathways; co-immunoprecipitation with clathrin heavy chain and caveolin-1; in vitro and in vivo (mouse) cigarette smoke exposure; apoptosis assay FASEB journal High 19423638
2009 Serpina1 protein in bone marrow extracellular fluid is predominantly produced by osteoblasts (OB), not hematopoietic cells. Quantitative RT-PCR showed high Serpina1 mRNA in OB; Western blot confirmed Serpina1 secretion by OB but not by hematopoietic cells; immunohistochemistry localized Serpina1 protein to OB lining the bone. This establishes that Serpina1 is synthesized in the osteoblastic stem cell niche and may regulate HSC maintenance. Quantitative RT-PCR; Western blot; immunohistochemistry on bone marrow sections Experimental hematology Medium 19375654
2010 Glycosylated AAT directly binds IL-8 (a CXCR1 ligand), and AAT-IL-8 complex formation prevents IL-8 interaction with CXCR1, thereby inhibiting CXCR1-mediated neutrophil chemotaxis. Additionally, AAT controls soluble immune complex (sIC)-induced neutrophil chemotaxis by inhibiting ADAM-17 enzymatic activity, thereby maintaining membrane expression of the GPI-anchored Fc receptor FcγRIIIb. These two distinct pathways of AAT-mediated neutrophil chemotaxis regulation were confirmed in AAT-deficient patients and restored by augmentation therapy. Binding assays (AAT-IL-8 complex formation); CXCR1 interaction studies; ADAM-17 enzymatic inhibition assay; FcγRIIIb membrane expression by flow cytometry; human patient samples before/after augmentation therapy The Journal of clinical investigation High 21060150
2014 A1AT is actively transported (transcytosed) across lung endothelial cells to the alveolar epithelium. Purified A1AT was taken up by confluent endothelial monolayers and secreted both apically and basolaterally. A1AT co-localized with Golgi in endothelium; inhibition of classical secretory pathway increased intracellular retention but promoted non-classical secretion via microparticle release. Polymerized A1AT or cigarette smoke extract impaired transcytosis. In vivo evidence was obtained by two-photon intravital microscopy in mice. Polarized transwell co-culture; confocal time-lapse microscopy; Golgi inhibition (tunicamycin); two-photon intravital microscopy in mice; microparticle analysis PloS one High 24743137
2015 Scavenger receptor B type I (SR-BI) mediates A1AT endocytosis by pulmonary endothelial cells. SR-BI immunoprecipitation identified binding to A1AT at the plasma membrane. Knockdown of SCARB1 expression, pretreatment with SR-B ligands (HDL or LDL), or neutralizing SR-BI antibodies reduced A1AT uptake by 30-50%. Scarb1 null mice exhibited decreased lung A1AT content following systemic A1AT administration and reduced anti-inflammatory effects of A1AT during cigarette smoke exposure. Transmission electron microscopy confirmed A1AT endocytosis in both clathrin-coated vesicles and caveolae. SR-BI immunoprecipitation; siRNA knockdown; competitive ligand pretreatment; neutralizing antibodies; Scarb1 knockout mice; transmission electron microscopy with colloidal gold-labeled A1AT American journal of physiology. Lung cellular and molecular physiology High 26092999
2016 NQO1 (NAD(P)H:quinone oxidoreductase 1) acts as an RNA-binding protein that binds the 3'UTR and coding region of SERPINA1 mRNA and enhances its translation without affecting mRNA levels. NQO1 silencing decreased polysome size on SERPINA1 mRNA and lowered A1AT protein abundance. Luciferase reporter analysis confirmed regulation through the SERPINA1 3'UTR. NQO1-knockout mice had reduced hepatic and serum A1AT levels and increased neutrophil elastase activity. RNP immunoprecipitation (RIP) and microarray; biotin pulldown of SERPINA1 mRNA regions; polysome profiling; luciferase reporter assay; NQO1 siRNA knockdown; NQO1-KO mice Free radical biology & medicine High 27515817
2017 The coding variant V213A (rs568223361) in SERPINA1 modulates AAT interaction with neutrophil elastase (NE) in lipoprotein-containing plasma. Quantitative microscale thermophoresis showed M1(A213) AAT has an almost twofold lower dissociation constant with NE in lipoprotein-containing (but not lipid-free) plasma. Hydrogen/deuterium exchange mass spectrometry revealed significant differences in global flexibility between V213 and A213 variants. The Val-213 variant shows stronger lipoprotein interaction and reduced global flexibility, improving local availability and reducing proteolytic inactivation by other proteases in atherosclerotic plaques. Quantitative microscale thermophoresis; hydrogen/deuterium exchange coupled mass spectrometry Proceedings of the National Academy of Sciences of the United States of America High 28265093
2017 The Trento variant of AAT (E75V) shows non-classical polymerization behavior distinct from Z (E342K) and S (E264V) variants. Trento AAT is efficiently secreted in cellular models but has compromised conformational stability. PAGE and ELISA revealed oligomeric species with different electrophoretic and immunorecognition profiles, including reduced recognition by conformational monoclonal antibodies 2C1 and 4B12. Structural analysis localized the 2C1 epitope between helices E and F and indicated that E75V disrupts a stabilizing interaction between helix C and the post-helix I loop, causing polymer formation through a different structural pathway. Cell expression models; PAGE; conformational antibody ELISA; epitope mapping; structural analysis The FEBS journal Medium 28504839
1994 Acetaldehyde (at 0.3–1.2 M concentrations) inhibits the anti-elastase activity of alpha-1-antitrypsin in biochemical assays, while equivalent concentrations of ethanol have no effect on elastase activity or A1AT function. This provides a biochemical mechanism by which alcohol metabolism may compound A1AT deficiency. In vitro elastase inhibition assay with purified A1AT and acetaldehyde/ethanol Alcohol (Fayetteville, N.Y.) Low 8060517
2000 Sodium citrate at low concentrations increases the conformational stability of alpha-1-antitrypsin without affecting inhibitory activity, as demonstrated by a 1.8 M increase in midpoint of guanidine hydrochloride-induced unfolding and ~30-fold decrease in heat inactivation rate at 0.5 M citrate. Citrate also increased the insertion rate of exogenous reactive-center loop peptide into the A beta-sheet, indicating structural changes in the sheet region despite unaltered tertiary structure by fluorescence and CD spectroscopy. Guanidine hydrochloride denaturation; heat inactivation kinetics; fluorescence spectroscopy; circular dichroism; exogenous peptide insertion assay; chymotrypsin inhibition assay Biochimica et biophysica acta Medium 10962087
2017 Carbamylated alpha-1-antitrypsin (Ca-A1AT) is an antigenic target of anti-carbamylated protein (anti-CarP) antibodies in rheumatoid arthritis patients. A1AT contains multiple surface lysines that are readily carbamylated. Mass spectrometry identified carbamylated A1AT in synovial fluid of an RA patient. This establishes A1AT as a post-translationally modified autoantigen in RA via carbamylation. Ion exchange chromatography fractionation; mass spectrometry for carbamylated protein identification; ELISA; synovial fluid mass spectrometry Journal of autoimmunity Medium 28291659
2022 The 5'-UTR of SERPINA1 NM_000295.4 transcript folds into a well-defined multi-helix structural domain that optimizes translation by promoting accessibility at the translation initiation site. Systematic destabilization of mRNA structure across the 5'-UTR showed that most structure-destabilizing mutations had no effect on or decreased translation despite disrupting local structure, because they retained global 5'-UTR structure. Mutations disrupting the helix anchoring the 5'-UTR domain created non-native structures forming a stable helix near the translation initiation site that decreases translation. SHAPE quantification of RNA structure; systematic mutagenesis across 5'-UTR; cap-dependent translation reporter assays; RNA structure analysis Nucleic acids research High 36107773
2021 miR-320c directly inhibits SERPINA1 expression in hepatic HepG2 cells via binding sites in the 3'UTR region of SERPINA1 mRNA. Overexpression of miR-320 family members in HepG2 cells led to inhibition of SERPINA1 expression. LPS treatment of HL60 cells increased miR-320c expression, suggesting inflammation-mediated regulation of A1AT through this miRNA. miRNA overexpression in HepG2 cells; quantitative PCR; LPS stimulation of HL60 cells; correlation with patient samples Archivos de bronconeumologia Medium 32439252 35698951
2024 Hepatic SerpinA1/A1AT functions as a hepatokine that improves energy and glucose metabolism by: (1) inducing proliferation of white and brown preadipocytes; (2) increasing UCP1 expression to promote mitochondrial activation in adipocytes; (3) forming a complex with the Eph receptor B2 (EphB2) and regulating its downstream signaling in adipocytes. Liver-specific SerpinA1 transgenic mice showed increased adipose browning, energy expenditure, and improved glucose tolerance. SerpinA1 knockout mice had decreased adipocyte mitochondrial function, impaired thermogenesis, obesity, and systemic insulin resistance. Liver-specific transgenic mice; SerpinA1 knockout mice; co-immunoprecipitation (SerpinA1-EphB2 complex); in vitro preadipocyte proliferation and UCP1 assays; metabolic phenotyping Nature communications High 39532838
2025 Hepatic A1AT controls the PR3/IL-32γ axis during MASH (metabolic dysfunction-associated steatohepatitis). In MASH, Kupffer cell-derived IL-1β transcriptionally inhibits A1AT expression via HNF4α. Loss of A1AT increases activity of proteinase 3 (PR3), a proinflammatory protease from monocyte-derived Kupffer cells. PR3 cleaves IL-32γ, converting it from an anti-inflammatory/antifibrogenic cytokine into a potent activator of Kupffer cells and failing to prevent hepatic stellate cell activation. In quintuple Serpina1a-e knockout mice, A1AT ablation worsened MASH; A1AT restoration or PR3 inhibition mitigated MASH. A PR3-resistant IL-32γ V104A mutation sustained IL-32γ's protective anti-MASH effects. Quintuple Serpina1a-e knockout mice; fast-food diet MASH model; cytokine array with PR3; IL-32γ V104A mutation; in vivo IL-32γ overexpression; A1AT/PR3 inhibitor treatment; hepatic stellate cell activation assays Experimental & molecular medicine High 39939782
2024 CEBPB transcription factor binds the SERPINA1 gene promoter and promotes its transcription, as demonstrated by ChIP and luciferase reporter assays. Overexpression of SERPINA1 in colorectal cancer cells induces nuclear translocation and phosphorylation of the p65 subunit through the PI3K/Akt/NF-κB pathway, promoting cell migration and proliferation. Knockdown of SERPINA1 attenuated PI3K/Akt/NF-κB signaling. ChIP assay; luciferase reporter assay; SERPINA1 overexpression and knockdown; PI3K/Akt/NF-κB pathway analysis; in vitro migration/invasion assays; in vivo liver metastasis model Cell death discovery Medium 38710698
2022 In trophoblast-derived HTR8/SVneo cells, siRNA knockdown of SERPINA1 revealed marked effects on regulation of the actin cytoskeleton pathway, Slit-Robo signaling, and extracellular matrix organization. Immunoelectron microscopy localized A1AT in villous trophoblasts and in decidual fibrinoid deposits in association with specific extracellular proteins, establishing a role for A1AT beyond protease inhibition in maintaining placental structural integrity. siRNA knockdown in HTR8/SVneo cells; pathway analysis; immunoelectron microscopy; placental proteomics and exon sequencing BMC medicine Medium 35477570
2021 In vitro, intra-articular and systemic administration of AAT reversed joint inflammation, nociception, and cartilage degradation in murine arthritis models. SERPINA1 transfection and recombinant AAT protein promoted chondrogenic differentiation in human chondrocytes through activation of PKA-dependent CREB signaling and inhibition of Wnt/β-catenin pathways, establishing a direct mechanistic pathway for AAT's chondroprotective effects. SERPINA1 transfection; recombinant AAT protein treatment; PKA/CREB signaling assays; Wnt/β-catenin pathway analysis; gene expression analysis (col2a1, acan, sox9, mmp13, adamts5); in vivo murine arthritis models FASEB journal Medium 33788977
1981 Alpha-1-antitrypsin inactivates urinary kallikrein, as demonstrated by an inverse relationship (r=0.84) between kallikrein activity and urinary A1AT concentration in patient samples, establishing renal kallikrein as a substrate/target of A1AT. Clinical urinary proteolytic activity assay (azocasein substrate with kallikrein); immunoassay for urinary A1AT; correlation analysis in 100 hypertensive/proteinuric/hematuria patients Klinische Wochenschrift Low 6973046

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2003 Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry. Nature biotechnology 1176 12754519
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2000 Structure of a serpin-protease complex shows inhibition by deformation. Nature 926 11057674
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