The degree of unsaturation of fatty acids in phosphatidylserine alters the rate of insulin aggregation and the structure and toxicity of amyloid aggregates

Abstract

Phosphatidylserine (PS) in the plasma membrane plays an important role in cell signaling and apoptosis. Cell degeneration is also linked to numerous amyloid diseases, pathologies that are associated with aggregation of misfolded proteins. In this work, we examine the effect of both saturated PS (DMPS) and unsaturated PS (DOPS and POPS) on the aggregation properties of insulin, as well as the structure and toxicity of insulin aggregates formed in the presence of these phospholipids. We found that the degree of unsaturation of fatty acids in PS alters the rate of insulin aggregation. We also found that toxicity of insulin–DMPS aggregates is significantly lower than the toxicity of DOPS– and POPS–insulin fibrils, whereas all these lipid‐containing aggregates exert lower cell toxicity than insulin fibrils grown in a lipid‐free environment.

Lipids uniquely alter secondary structure and toxicity of lysozyme aggregates

“…These findings show that lipids can uniquely shorten and delay the lag phase of lysozyme aggregation or have no effect on t lag of the protein assembly into fibrils. Similar results were recently reported by Matveyenka and co‐workers for insulin 34,35 . Specifically, it was found that PC strongly inhibited insulin aggregation, whereas both CL and PS strongly accelerated insulin fibril formation.…”

“…This finding suggests that lysozyme aggregation in the presence of lipids yields a higher amount of ThT active protein aggregates. Similar results were recently reported by Matveyenka and co‐workers for insulin 34,35 . Specifically, it was found that such an increase in the ThT intensity is associated with drastic changes in the morphology and secondary structure of inulin aggregates that were grown in the presence of PS and CL compared to the insulin fibrils formed in the lipid‐free environment.…”

“…The structural heterogeneity can be determined by variability in the intensity in observed vibrational bands that correspond to lipids (~800 and 1000-1200 cm −1 ) and protein (1555 cm −1 (amide II) and 1630-1595 cm −1 (amide I)) vibrations. 34,35,48,49 We found that lysozyme aggregates grown in the lipid-free environment exhibited very little if any structural heterogeneity. However, structural heterogeneity of Lys:PS, Lys:CL, as well as Lys:PC:CL (1:0.5:0.5) and Lys:PC:CL (1:0.8:0.2) was found to be substantially larger.…”

“…Similar results were recently reported by Matveyenka and co-workers for insulin. 34,35 Specifically, it was found that PC strongly inhibited insulin aggregation, whereas both CL and PS strongly accelerated insulin fibril formation.…”

Length and Unsaturation of Fatty Acids of Phosphatidic Acid Determines the Aggregation Rate of Insulin and Modifies the Structure and Toxicity of Insulin Aggregates

“…6 In addition to PA, plasma membranes contain phosphatidylcholine (PC), phosphatidylserine (PS), and other phospholipids. 5 A growing body of evidence suggests that both PC and PS can uniquely alter the aggregation properties of amyloid-associated proteins that include α-synuclein (α-Syn), 7 insulin 8,9 islet amyloid polypeptide protein, 10 and amyloid β peptide. 11 Abrupt aggregation of these proteins determines the onset and progression of amyloid diseases, including diabetes type 2 and Alzheimer's and Parkinson's diseases.…”