Acute phase proteins are major clients for the chaperone action of α2-macroglobulin in human plasma

Abstract

Extracellular protein misfolding is implicated in many age-related diseases including Alzheimer's disease, macular degeneration and arthritis. In this study, putative endogenous clients for the chaperone activity of α₂-macroglobulin (α₂M) were identified after human plasma was subjected to physiologically relevant sheer stress at 37 °C for 10 days. Western blot analysis showed that four major acute phase proteins: ceruloplasmin, fibrinogen, α₁-acid glycoprotein and complement component 3, preferentially co-purified with α₂M after plasma was stressed. Furthermore, the formation of complexes between α₂M and these putative chaperone clients, detected by sandwich ELISA, was shown to be enhanced in response to stress. These results support the hypothesis that α₂M plays an important role in extracellular proteostasis by sequestering misfolded proteins and targeting them for disposal, particularly during acute phase reactions.

Hypochlorite-induced structural modifications enhance the chaperone activity of human α2-macroglobulin

“…Inflammation is a state in which many stresses capable of inducing protein misfolding and aggregation are elevated; therefore, it is likely that proteostasis mechanisms will be enhanced during inflammatory events. Moreover, it has been shown that many acute-phase proteins are susceptible to stress-induced misfolding and major endogenous clients for holdase chaperones in human blood plasma (65)(66)(67). To survive periods of increased physiological stress, cells use several different strategies to prevent the accumulation of misfolded proteins (68)(69)(70)(71).…”

How schistosomes alter the human serum proteome

“…On the other hand, α2M can also inhibit the blood clot-promoting enzyme thrombin, an activity that schistosomes would likely not wish to impede. It is worth pointing out that α2M also acts as a chaperone; the protein plays an important role in extracellular proteostasis by sequestering misfolded proteins that are found in “stressed” extracellular fluids [19]. Clusterin too can act as an extracellular chaperone [20] and, as revealed in this work, schistosomes also impact this protein.…”

Proper antiviral therapy for hepatitis B virus-associated acute-on-chronic liver failure

“…Glutamyl residue may form a covalent linkage with lysine of proteinase and the cysteinyl residue may bind cytokines (Athippozhy et al, 2011) or A chain of the plant toxin, ricin (Pop et al, 2005). The Receptor‐Binding Site : It is a 138 amino acid sequence present at the C‐terminal of each subunit of α 2 M. The receptor‐binding site is exposed only after conformational change in the structure of α 2 M, so that only the α 2 M–proteinase complex is cleared, and not the native α 2 M. The binding site is recognized by the 600 kDa α 2 M receptor which is a cell surface glycoprotein (Strickland et al, 1990; Wyatt and Wilson, 2012), a member of low‐density lipoprotein (LDL) superfamily (Pires et al, 2012; Wild et al, 2012). The Transglutaminase Reactive Site : A transglutaminase reactive site is present in close proximity to the bait region, 20 amino acids upstream from the primary proteinase cleavage site that is accessible in the native α 2 M. Metalloprotein : α 2 M is a metalloprotein and is a major zinc‐binding plasma protein.…”

“…The Receptor‐Binding Site : It is a 138 amino acid sequence present at the C‐terminal of each subunit of α 2 M. The receptor‐binding site is exposed only after conformational change in the structure of α 2 M, so that only the α 2 M–proteinase complex is cleared, and not the native α 2 M. The binding site is recognized by the 600 kDa α 2 M receptor which is a cell surface glycoprotein (Strickland et al, 1990; Wyatt and Wilson, 2012), a member of low‐density lipoprotein (LDL) superfamily (Pires et al, 2012; Wild et al, 2012). …”

“…The mammalian receptor for proteinase‐reacted α 2 M is a low‐density lipoprotein receptor related protein (LRP/α 2 M‐R; Strickland et al, 1990; Pandey et al, 2008; Fujiyoshi et al, 2011; Larios and Marzolo, 2012; Wyatt and Wilson, 2012) and belongs to the low‐density lipoprotein receptor (LDLR) family (Borth et al, 1994; Truman et al, 2012). The LRP/α 2 M‐R is a 600 kDa glycoprotein that undergoes proteolysis in the trans‐Golgi and is expressed as a non‐covalently associated heterodimer of 515 and 85 kDa.…”