On the molecular mechanism that links glycation with aggregation: the case of lysozyme glycated with ribose

Protein glycation (PG) usually induces the loss of protein function and consequently, the development of diabetes-related diseases1. It has been assumed that this process occurs as a result of a structural modification induced by PG, which is also able to trigger protein aggregation. Therefore, neurodegenerative disorders such as Parkinson or Alzheimer diseases increase their prevalence under diabetes mellitus. Trying to describe in detail the molecular mechanism that links PG with protein aggregation we have studied the glycation of lysozyme (HEWL) with ribose2. HEWL has been used as a model since it holds a reduced aggregation tendency under its native state and possesses putative glycation targets (lysine and arginine)3. On the other hand, ribose induces protein aggregation4 and it physiological concentration rapidly rises in diabetic patients5. Through the combination of different biophysical techniques (NMR, CD, SAXS, etc.), we have proved that HEWL glycation mediated by ribose mainly occurs on lysine without altering the protein structure. However, glycation induces a change on the overall protein charge generating different hydrophobic patches which are responsible for the native aggregation of glycated HEWL. This aggregation process initiates with the formation of soluble oligomers which finally assemble to form insoluble aggregates.