Growth of β2-microglobulin-related amyloid fibrils by non-esterified fatty acids at a neutral pH

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The relationship between various amyloidoses and chaperones is gathering attention. In patients with dialysis-related amyloidosis, ␣ 2 -macroglobulin (␣2M), an extracellular chaperone, forms a complex with ␤ 2 -microglobulin (␤2-m), a major component of amyloid fibrils, but the molecular mechanisms and biological implications of the complex formation remain unclear. Here, we found that ␣2M substoichiometrically inhibited the ␤2-m fibril formation at a neutral pH in the presence of SDS, a model for anionic lipids. Binding analysis showed that the binding affinity between ␣2M and ␤2-m in the presence of SDS was higher than that in the absence of SDS. Importantly, SDS dissociated tetrameric ␣2M into dimers with increased surface hydrophobicity. Western blot analysis revealed that both tetrameric and dimeric ␣2M interacted with SDS-denatured ␤2-m. At a physiologically relevant acidic pH and in the presence of heparin, ␣2M was also dissociated into dimers, and both tetrameric and dimeric ␣2M interacted with ␤2-m, resulting in the inhibition of fibril growth reaction. These results suggest that under conditions where native ␤2-m is denatured, tetrameric ␣2M is also converted to dimeric form with exposed hydrophobic surfaces to favor the hydrophobic interaction with denatured ␤2-m, thus dimeric ␣2M as well as tetrameric ␣2M may play an important role in controlling ␤2-m amyloid fibril formation.A number of proteins and peptides can misfold into ␤-sheetrich structures, called amyloid fibrils (1). The deposition of amyloid fibrils in intra-and extracellular spaces is responsible for more than 40 serious diseases, including Alzheimer and Parkinson diseases and dialysis-related amyloidosis (DRA) 2 (1). ␤ 2 -Microglobulin (␤2-m) is a major structural component of amyloid fibrils in DRA, a common and serious complication in long term hemodialysis patients (2). The formation of ␤2-m amyloid fibrils is thought to be induced by partial unfolding of ␤2-m (3, 4). Several groups have established conditions under which ␤2-m amyloid fibril formation occurs at a neutral pH (5-11). We found that ␤2-m amyloid fibrils are formed at a neutral pH in the presence of SDS (11). SDS below its critical micelle concentration unfolds the compact structure of ␤2-m to an amyloidogenic conformer and stabilizes the extended amyloid fibrils. SDS is an anionic detergent that mimics some characteristics of biological membranes and is considered to be a good model for anionic lipids. We recently reported that some lysophospholipids, especially lysophosphatidic acid as well as nonesterified fatty acids induce the extension of ␤2-m amyloid fibrils at a neutral pH by partially unfolding the compact structure of ␤2-m to an amyloidogenic conformer as well as by stabilizing the extended fibrils (6, 8). Although many groups have proposed the mechanisms by which ␤2-m amyloid fibrils are formed under physiological conditions, the biological machineries to inhibit the formation and deposition of ␤2-m amyloid fibrils are poorly understood (12).␣ 2 -Macroglobulin (...

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confidence: 75%

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confidence: 99%

Inhibition of β2-Microglobulin Amyloid Fibril Formation by α2-Macroglobulin

Ozawa

Hara

Lee

et al. 2011

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“…Fatty acids, such as palmitic acid, stearic acid, and oleic acid have been reported to be present in the serum in a molar ratio of 3:1:3 (2,27,28), and the mixture of these fatty acids is known to promote the amyloid fibril formation of ␤2m (7). In the present study, we have investigated the effect of the extracellular protein haptoglobin (Hp2-2 isoform) on the fatty acid-promoted de novo fibril formation of ␤2m.…”

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confidence: 99%

“…Therefore, understanding the factors (especially from plasma) that modulate the amyloid fibril formation of ␤2m is important in the context of ␤2m amyloidosis. Fatty acids, lysophospholip-ids (1,7,8), glycosaminoglycan, and proteoglycan are among the factors that are known to promote the fibril formation of ␤2m (9 -11). The details of plasma factors that suppress or inhibit the fibril formation are not completely understood.…”

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confidence: 99%

The Extracellular Chaperone Haptoglobin Prevents Serum Fatty Acid-promoted Amyloid Fibril Formation of β2-Microglobulin, Resistance to Lysosomal Degradation, and Cytotoxicity

Sultan¹,

Raman

Rao

et al. 2013

Background:The role of chaperones in extracellular space is important. Haptoglobin, an extracellular chaperone, is investigated in the context of ␤ 2 -microglobulin amyloidosis. Results: Haptoglobin interacts with prefibrillar species, facilitates intracellular degradation, and prevents formation of cytotoxic ␤2m fibrils. It exhibits pH-dependent chaperone activity. Conclusions: Haptoglobin is an extracellular chaperone for ␤ 2 -microglobulin under normal and inflammation-induced acidosis conditions. Significance: Haptoglobin has promising therapeutic implications in extracellular protein deposition diseases.

“…The structure of the N-terminal domain of ccd-Angptl4 appeared to be rather unstable. Several previous studies report that lipid-like compounds unfold proteins of different kinds to less structured states (52,53), probably because hydrophobic interaction is often central for protein packing.…”

Section: Proteinmentioning

confidence: 99%

Fatty Acids Bind Tightly to the N-terminal Domain of Angiopoietin-like Protein 4 and Modulate Its Interaction with Lipoprotein Lipase

Robal

Larsson

Martin

et al. 2012

Background: Angiopoietin-like protein 4 regulates plasma triglyceride metabolism by modulating the activity of lipoprotein lipase. Results: Fatty acids bind tightly to the N-terminal domain of angiopoietin-like protein 4 and reduce its effect on lipoprotein lipase. Conclusion: Fatty acids play a role in modulating the effects of angiopoietin-like protein 4. Significance: A novel mechanism for regulation of the action of angiopoietin-like protein 4 is proposed.