title: Insulin glycation by methylglyoxal results in native-like aggregation and inhibition of fibril formation.
abstract: BACKGROUND
  Insulin is a hormone that regulates blood glucose homeostasis and is a central protein in a medical condition termed insulin injection amyloidosis. It is intimately associated with glycaemia and is vulnerable to glycation by glucose and other highly reactive carbonyls like methylglyoxal, especially in diabetic conditions. Protein glycation is involved in structure and stability changes that impair protein functionality, and is associated with several human diseases, such as diabetes and neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Familiar Amyloidotic Polyneuropathy. In the present work, methylglyoxal was investigated for their effects on the structure, stability and fibril formation of insulin.
  
  
  RESULTS
  Methylglyoxal was found to induce the formation of insulin native-like aggregates and reduce protein fibrillation by blocking the formation of the seeding nuclei. Equilibrium-unfolding experiments using chaotropic agents showed that glycated insulin has a small conformational stability and a weaker dependence on denaturant concentration (smaller m-value). Our observations suggest that methylglyoxal modification of insulin leads to a less compact and less stable structure that may be associated to an increased protein dynamics.
  
  
  CONCLUSIONS
  We propose that higher dynamics in glycated insulin could prevent the formation of the rigid cross-β core structure found in amyloid fibrils, thereby contributing to the reduction in the ability to form fibrils and to the population of different aggregation pathways like the formation of native-like aggregates.
authors.affiliation: Centro de Investigação Interdisciplinar Egas Moniz, Instituto Superior das Ciências da Saúde Egas Moniz, Campus Universitário, Monte da Caparica 2829-511 Caparica, Portugal.
authors.forename: Luis M A
authors.initials: LM
authors.lastname: Oliveira
authors.forename: Ana
authors.initials: A
authors.lastname: Lages
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Gomes
authors.forename: Henrique
authors.initials: H
authors.lastname: Neves
authors.forename: Carlos
authors.initials: C
authors.lastname: Família
authors.forename: Ana V
authors.initials: AV
authors.lastname: Coelho
authors.forename: Alexandre
authors.initials: A
authors.lastname: Quintas
mesh_terms: D000595:Amino Acid Sequence; D004305:Dose-Response Relationship, Drug; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000737:chemistry* / Q000378:metabolism*; D055503:Protein Multimerization / Q000187:drug effects*; D055550:Protein Stability / Q000187:drug effects; D017433:Protein Structure, Secondary; D011765:Pyruvaldehyde / Q000494:pharmacology*
chemical_list: D007328:Insulin; D011765:Pyruvaldehyde