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The Crystal Structure of Human α2‐Macroglobulin Reveals a Unique Molecular Cage

Published on Apr 2, 2012in Angewandte Chemie12.257
· DOI :10.1002/anie.201108015
A. Marrero8
Estimated H-index: 8
(CSIC: Spanish National Research Council),
Stéphane Duquerroy21
Estimated H-index: 21
(University of Paris-Sud)
+ 6 AuthorsF. Xavier Gomis-Rüth31
Estimated H-index: 31
(CSIC: Spanish National Research Council)
Abstract
  • References (23)
  • Citations (61)
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References23
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The plasmin–antiplasmin system plays a key role in blood coagulation and fibrinolysis. Plasmin and α2-antiplasmin are primarily responsible for a controlled and regulated dissolution of the fibrin polymers into soluble fragments. However, besides plasmin(ogen) and α2-antiplasmin the system contains a series of specific activators and inhibitors. The main physiological activators of plasminogen are tissue-type plasminogen activator, which is mainly involved in the dissolution of the fibrin polyme...
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#1Chuan-ju Liu (NYU: New York University)H-Index: 39
Breakdown of the extracellular matrix leading to loss of articular cartilage and bone is a characteristic feature of arthritis. The author of this Review discusses the potential role of two novel members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, ADAMT-7 and ADAMTS-12, in the degradation of cartilage oligomeric matrix protein, and suggests that that α2-macroglobulin and granulin-epithelin precursor could represent their endogenous inhibitors.
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#1Ninh Doan (UIC: University of Illinois at Chicago)H-Index: 2
#2Peter G. W. Gettins (UIC: University of Illinois at Chicago)H-Index: 37
Human α2M (α2-macroglobulin) and the complement components C3 and C4 are thiol ester-containing proteins that evolved from the same ancestral gene. The recent structure determination of human C3 has allowed a detailed prediction of the location of domains within human α2M to be made. We describe here the expression and characterization of three α2M domains predicted to be involved in the stabilization of the thiol ester in native α2M and in its activation upon bait region proteolysis. The three ...
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#1Bert J. C. Janssen (UU: Utrecht University)H-Index: 18
#2Eric G. Huizinga (UU: Utrecht University)H-Index: 28
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Structures of complement component C3 provide insights into the function and evolution of immunity
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The recent explosion in our understanding of Alzheimer’s disease (AD) at both the molecular and biochemical levels is due, in large part, to the successful utilization of genetic and genomic analyses over the past two decades. Initial positional cloning efforts of the 80s and 90s led to the identification of three genes, amyloid precursor protein (APP) and presenilins 1 and 2 (PSEN1 and PSEN2), that can harbor mutations leading to the rare, early-onset ( 60 years) familial form of AD. Phenotypic...
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Abstract Three-dimensional electron microscopy reconstructions of the human α2-macroglobulin (α2M) dimer and chymotrypsin-transformed α2M reveal the structural arrangement of the two dimers that comprise native and proteinase-transformed molecules. They consist of two side-by-side extended strands that have a clockwise and counterclockwise twist about their major axes in the native and transformed structures, respectively. This and other studies show that there are major contacts between the two...
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#1P.B. Armstrong (MBL: Marine Biological Laboratory)H-Index: 6
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All animals and plants have immune systems that protect them from the diversity of pathogens that would otherwise threaten their survival. The different components of the immune system may inactivate the pathogens themselves or promote the inactivation and clearance of toxic products produced by the pathogens. An important category of virulence factors of bacterial and prokaryotic pathogens are the proteases, which act to facilitate the invasion of the pathogens and to promote their destructive ...
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: A brief historical introduction to the matrix metalloproteinase (MMP) field, which began in 1962, is followed by an overview of the inhibition of these proteases by natural inhibitors such as α2 macroglobulin and the TIMPs (tissue inhibitors of metalloproteinases) and by synthetic inhibitors, which are largely chelating agents. The latter include thiol, alkylcarbonyl, phosponamidate and hydroxamate compounds, as well as the tetracyclines. A review of the most recent progress concludes with pro...
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#1Lasse Jenner (AU: Aarhus University)H-Index: 9
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Abstract Background: The large plasma proteinase inhibitors of the α 2 -macroglobulin superfamily inhibit proteinases by capturing them within a central cavity of the inhibitor molecule. After reaction with the proteinase, the α -macroglobulin–proteinase complex binds to the α -macroglobulin receptor, present in the liver and other tissues, and becomes endocytosed and rapidly removed from the circulation. The complex binds to the receptor via recognition sites located on a separate domain of app...
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#1Hyun Kyu Song (UPR-RP: UPRRP College of Natural Sciences)H-Index: 37
#2Se Won Suh (UPR-RP: UPRRP College of Natural Sciences)H-Index: 40
Abstract The Kunitz-type trypsin inhibitor from soybean (STI) consists of 181 amino acid residues with two disulfide bridges. Its crystal structures have been determined in complex with porcine pancreatic trypsin in two crystal forms (an orthorhombic form at 1.75 A resolution and a tetragonal form at 1.9 A) and in the free state at 2.3 A resolution. They have been refined to crystallographic R -values of 18.9%, 21.6% and 19.8%, respectively. The three models of STI reported here represent a sign...
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AbstractAutoimmune responses against post-translationally modified antigens are a hallmark of several autoimmune diseases. In this work, we have studied the changes in alpha-2-macroglobulin (α2M) u...
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It has been reported that Cu(II) ions in human blood are bound mainly to serum albumin (HSA), ceruloplasmin (CP), alpha-2-macroglobulin (α2M) and His, however, data for α2M are very limited and the thermodynamics and kinetics of the copper distribution are not known. We have applied a new LC-ICP MS-based approach for direct determination of Cu(II)-binding affinities of HSA, CP and α2M in the presence of competing Cu(II)-binding reference ligands including His. The ligands affected both the rate ...
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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, SLP...
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Alpha-macroglobulins are ancient proteins that include monomeric, dimeric, and tetrameric family members. In humans, and many other mammals, the predominant alpha-macroglobulin is alpha-2-macroglobulin (α2M), a tetrameric protein that is constitutively abundant in biological fluids (e.g., blood plasma, cerebral spinal fluid, synovial fluid, ocular fluid, and interstitial fluid). α2M is best known for its remarkable ability to inhibit a broad spectrum of proteases, but the full gamut of its activ...
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