Disease relevance of A2M

• Inhibition of t-PA and alpha 2M* binding to LRP/alpha 2MR on rat hepatoma MH1C1 cells are shown to require amino acid residues 18-24 and 100-107 on the 39-kDa protein [1].
• Preincubation of permeabilized macrophages with GDP beta S abrogated the effects of GTP gamma S. Our results suggest that the signaling alpha 2M receptor is coupled to a pertussis toxin-insensitive G protein and possibly to a cholera toxin-sensitive G protein [2].
• Ni2+ also inhibited the binding of trypsin-activated alpha 2-macroglobulin to SMC but did not affect the binding of RAP, Pseudomonas exotoxin A, or low-density lipoproteins [3].
• Polymyxin B-conjugated alpha 2-macroglobulin as an adjunctive therapy to sepsis: Modes of action and impact on lethality [4].
• Serum alpha 2M was greater in dialysis-related amyloidosis than in control patients (t = 2.35; P < 0.026) [5].

Psychiatry related information on A2M

• alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD) [6].
• We did find evidence for association between the A2M D-allele and Lewy body dementia [7].
• Complexing of tissue plasminogen activator with PAI-1, alpha 2-macroglobulin, and C1-inhibitor: studies in patients with defibrination and a fibrinolytic state after electroshock or complicated labor [8].
• alpha 1-Antitrypsin phenotypes and alpha 2-macroglobulin concentrations were determined for an Australian population of 286 Down's syndrome patients, 296 newborn babies, and 193 patients with non-specific mental retardation [9].
• Increased alpha-2-macroglobulin in opiate addicts: further evidence of an alteration in the coagulation system due to opiate addiction [10].

High impact information on A2M

• Alpha-2 macroglobulin gene and Alzheimer disease [11].
• The observed association of A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which we were unable to confirm in this sample [12].
• To study the intracellular sorting of internalized ligands and receptors, we examined the pathways of two ligands: transferrin, which is recycled, and alpha 2-macroglobulin (alpha 2M), which is degraded [13].
• Rhodamine-labeled alpha 2M is found in a punctate pattern [13].
• Using image intensified fluorescence microscopy and digital image analysis, we determined that the F-Tf containing structure has a pH of 6.4 +/- 0.2, while endocytic vesicles containing F-alpha 2M have a pH of 5.4 +/- 0 [13].

Chemical compound and disease context of A2M

• Ni2+ inhibited all of the specific binding of radiolabeled methylamine-activated alpha 2-macroglobulin (125I-alpha 2-M*) to rabbit aortic smooth muscle cells (SMC), rat hepatoma Fu5AH, and mouse fibroblast L cells [3].
• A modified human alpha 2-macroglobulin derivative that binds tumor necrosis factor-alpha and interleukin-1 beta with high affinity in vitro and reverses lipopolysaccharide toxicity in vivo in mice [14].
• The mutant alpha 2M was intracellularly active in COS-1 cells in inhibiting the endogenous processing of the soluble substrates for furin (von Willebrand factor, transforming growth factor beta1 and a soluble form of the envelope glycoprotein gp160 from HIV-1) but not the membrane-bound form of gp160 [15].
• Turnover of 125I labeled alpha 2M and alpha 1-I3 was then measured in controls, NAR and in two models of the nephrotic syndrome in rats (Heymann nephritis, HN; adriamycin-induced, ADR), yielding fractional catabolic rates (FCR), which at steady state equals synthesis [16].
• Temperature-dependent biosynthesis of thiol esters in baculovirus recombinant alpha 2M and PZP [17].

Biological context of A2M

• We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule [6].
• RESULTS: Comparison of allele, genotype, and haplotype frequencies for polymorphisms in A2M revealed no significant differences between patients and control subjects [18].
• We have prepared conjugates of polymyxin B (PMB) and the cytokine binding protein alpha2-macroglobulin (A2M) [4].
• We analyzed the frequency of two polymorphisms in the A2M (Val 1000 Ile, Exon 18 del), and one polymorphism in the LRP (A216V) gene in a case control study involving 326 MS patients, and 290 controls, all defined for the expression of HLA-DR15 [19].
• We examined the distribution of A2M genotypes and alleles in a cohort of 146 AD patients and 160 age-matched non-demented individuals [20].

Anatomical context of A2M

• Bovine milk LPL displaced both 125I-labeled alpha 2M* and 39-kDa alpha 2M receptor-associated protein (RAP) from the surface of cultured mutant fibroblasts lacking LDL receptors with apparent KI values at 4 degrees C of 6.8 and 30 nM, respectively [21].
• We conclude that macrophages contain a second alpha 2M receptor that is G protein-coupled [2].
• In addition, 125I-bFGF bound to alpha 2M has decreased ability to stimulate plasminogen activator production in bovine capillary epithelial cells [22].
• Here we demonstrate that complexes formed by cruzipain and alpha 2-macroglobulin (alpha 2M) are efficiently internalized by human monocytes, and that this process results in enhanced presentation of cruzipain peptides to CD4+ T cells from CDP [23].
• alpha 2-Macroglobulin synthesis by the human monocytic cell line THP-1 is differentiation state-dependent [24].

Associations of A2M with chemical compounds

• In addition, the present study shows that the valine to isoleucine (Val1000Ile) polymorphism of A2M is linked with AGD (P=0.03) [25].
• Methylamine, which blocks protease binding to alpha 2M, increases the amount of 125I-bFGF that can be bound 2-fold [22].
• Vascular endothelial growth factor is inactivated by binding to alpha 2-macroglobulin and the binding is inhibited by heparin [26].
• Furthermore, alpha 2M interfered with the internalization of beta-VLDL+E and subsequent induction in the cholesterol esterification by these cells [27].
• Complex formation is complete after 4 h and is inhibited by pretreating alpha 2M with dithiothreitol, iodoacetamide, iodoacetic acid, and N-ethylmaleimide [22].

Physical interactions of A2M

• A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP [6].
• Thus, our studies demonstrate several specific regions on the 39-kDa protein which are required for the inhibition of t-PA and alpha 2M* binding to LRP/alpha 2MR [1].
• These findings indicate that "F" alpha 2M interacts with IL-1 beta through a thiol-disulfide exchange reaction [28].
• When the macrophages were incubated with(125)I-rhIL-8-alpha-2-M complexes there was a significant amount of IL-8 associated with the cells [29].
• The PSA bound to alpha 2-M is caged by the inhibitor and thus escapes detection by antibodies [30].

Enzymatic interactions of A2M

• Although at a drastically reduced rate, high molecular weight kininogen was cleaved by alpha 2M-bound kallikrein [31].

Regulatory relationships of A2M

• The binding of 125I-VEGF to alpha 2M was partially inhibited by an excess of basic fibroblast growth factor [26].
• Although APOE epsilon4 clearly showed higher frequency in LOAD (0.34) than that in controls (0.09), giving an odds ratio of 5.14 (95% confidence interval, 2.31-11.76), neither ACT nor A2M showed statistically significant difference between LOAD and controls regardless of APOE carrier status [32].
• Since in the same cells IFN gamma also up-regulates alpha 2 macroglobulin, this effect may be due to an augmented degradation of the receptor during its recycling [33].
• Decreased alpha 2M concentration typically results from enhanced clearance of alpha 2M-proteinase complex and occurs in states of increased proteolytic activity, e.g. pancreatitis [34].
• LDL-R-related protein plays an important role in the clearance of plasma-activated alpha 2-macroglobulin and apolipoprotein E-enriched lipoproteins [35].

Other interactions of A2M

• Activated C3 and alpha 2M may function as IL-1 beta carrier proteins in biologic fluids, in addition to their other physiologic roles [36].
• The findings provide evidence that the alpha 2M receptor and LRP are the same molecule [37].
• It is possible that heparin-like molecules released from extracellular matrixes could prevent the inactivation of VEGF by alpha 2M resulting in the potentiation of processes such as tumor angiogenesis [26].
• This multifunctional receptor is the major neuronal receptor both for apolipoprotein E (apoE, protein; APOE, gene) and for alpha2-macroglobulin (alpha2M, protein; A2M, gene), and it mediates clearance of apoE/A beta and alpha2M/A beta complexes [38].
• Inhibition experiments indicated that the streptococcal binding site for alpha 2M differed from the receptors for immunoglobulin G, fibrinogen, aggregated beta 2-microglobulin, albumin, and fibronectin [39].

Analytical, diagnostic and therapeutic context of A2M

• An additional component of this receptor system is a 39-kDa polypeptide that co-purifies with the alpha 2M receptor during affinity chromatography [37].
• Further evidence comes from immunoprecipitation experiments using a monoclonal antibody specific for the alpha 2M receptor that show this molecule, like LRP, to contain two polypeptides of approximately 420 and 85 kDa that are noncovalently associated [37].
• Plasma samples which were subjected to non-denaturing PAGE and autoradiography demonstrated binding of both growth factors exclusively to the slow-form of alpha 2M [40].
• By immunoelectron microscopy we found that after 30 min at 37 degrees C most of the detected alpha 2M* (70% of the total gold particles) was inside the cells and associated with endosomal vesicles [41].
• The cleavage site of PSA in alpha 2-M was analyzed by SDS-PAGE and microsequencing [30].

References