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RESEARCH PROGRAM
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Research Units
Similar research programs:
- 1 - Molecular features of protein conformational diseases. Role of environmental factors on the structural changes of proteins for the design and the synthesis of agents with antiaggregating, antioxidant, antiglycating and chelating activity and for application in diagnostics.
- 2 - INTERACTION PARTNERS OF AMYLOIDOGENIC PROTEINS TO STUDY MISFOLDING AND AGGREGATION PROCESSES; POSSIBLE APPLICATIONS
- 3 - Theoretical and experimental approach to non-native states of proteins: formation of amyloid fibrils, unstructured and unfolded proteins.
- 4 - Role of metals – Ubiquitin/Proteasome interaction in the pathogenesis of conformational diseases
- 5 - Identification of folding and misfolding determinants by site-directed mutagenesis.
- 6 - Protein folding and aggregation: a theoretical-experimental approach
- 7 - Chemical processes and structural modifications in neurodegeneration
- 8 - Protein misfolding and amyloid formation: studies on the molecular basis of the appearance and aggregation of toxic conformers and on their interaction with either synthetic surfaces and cellular and tissue targets
- 9 - Protein interactomes: unravelling cellular networks in different pathophysiological conditions
- 10 - A multidisciplinary approach to the study of in vivo and vitro aggregation of polyglutamine-containing proteins. Role of molecular and environmental factors.
Scientific and education field classification
- Field: Scienze biologiche
International Patent Classification
- CHEMISTRY; METALLURGY
- ORGANIC CHEMISTRY (such compounds as the oxides, sulfides, or oxysulfides of carbon, cyanogen, phosgene, hydrocyanic acid or salts thereof C01; products obtained from layered base-exchange silicates by ion-exchange with organic compounds such as ammonium, phosphonium or sulfonium compounds or by intercalation of organic compounds C01B33/44; macromolecular compounds C08; dyes C09; fermentation products C12; fermentation or enzyme-using processes to synthesise a desired chemical compound or composition or to separate optical isomers from a racemic mixture C12P; production of organic compounds by electrolysis or electrophoresis C25B3/00, C25B7/00)
- PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- ORGANIC CHEMISTRY (such compounds as the oxides, sulfides, or oxysulfides of carbon, cyanogen, phosgene, hydrocyanic acid or salts thereof C01; products obtained from layered base-exchange silicates by ion-exchange with organic compounds such as ammonium, phosphonium or sulfonium compounds or by intercalation of organic compounds C01B33/44; macromolecular compounds C08; dyes C09; fermentation products C12; fermentation or enzyme-using processes to synthesise a desired chemical compound or composition or to separate optical isomers from a racemic mixture C12P; production of organic compounds by electrolysis or electrophoresis C25B3/00, C25B7/00)
Geographical classification
- Region: Veneto
Bibliografia
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22. Fandrich, M., Forge, V., Buder, K., Kitter, M., Dobson, C.M., and Dieckmann, S. (2003) Myoglobin forms amyloid fibrils by association of unfolded polypeptide segments. Proc. Natl. Acad. Sci. USA 100, 15463–15468.
23. Sirangelo, I., Malmo, C., Casillo, M., Mezzogiorno, A., Papa, M., and Irace, G. (2002). Tryptophanyl substitutions in apomyoglobin determine protein aggregation and amyloid-like fibril formation at physiological pH. J. Biol. Chem. 277, 45887–45891.
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Keywords
PROTEIN FOLDING, PROTEIN AGGREGATION, APOMYOGLOBIN, BIOSPECTROSCOPY, LIMITED PROTEOLYSIS, AMYLOIDOSIS AND PRION DISEASESAMYLOID AGGREGATION OF APOMYOGLOBIN: MOLECULAR MECHANISMS AND IDENTIFICATION OF AMYLOIDOGENIC AND CYTOTOXIC POLYPEPTIDE FRAGMENTS
Università degli Studi di PadovaAbstract
Protein aggregation cause the formation of fibrillar aggregates or amyloid precipitates that characterize the group of human diseases known as amyloidoses. Despite a very intensive research of the last years, a detailed understanding of the molecular principles underlying the transformation of soluble proteins into amyloid aggregates is still lacking. The proteins capable of forming amyloid fibrils are very diverse and do not consist only of proteins involved in severe debilitating diseases such as Alzheimer’s and prion diseases, but also of non-pathogenic proteins and even short peptides. However, X-ray fiber diffraction data indicate that all amyloid fibrils share a cross-beta structure, regardless of the native fold or amino acid sequence of the otherwise soluble protein or peptide. Thus, an increasingly adopted view is that the ability to form amyloid fibrils can be a general property of proteins and peptides under suitable experimental conditions.Considering the generic nature of amyloid structure, it can be proposed that an in-depth study of protein aggregation processes using one model protein system could establish principles that are generally applicable to all other amyloid-forming proteins. For this reason, in this Project we aim to use the 153-residue protein apomyoglobin (apoMb, myoglobin without the heme) as a model protein for unravelling features of protein fibrillogenesis, even if this protein does not seem to be associated with any disease >>>
Principal Investigator
Angelo Fontana Università degli Studi di PADOVAResearch Objectives
A considerable body of evidence suggests that amyloid formation generally occurs through a nucleation-dependent polymerisation mechanism. This means that, under destabilising conditions and above a critical protein concentration, a protein species can form a nucleus given by the association of a number of protein molecules (pre-fibrillar state) and then the fibrils are formed by additional protein association and structural rearrangements. Indeed, protofibrils and oligomers are metastable assemblies observed during the growth of amyloid fibrils of a number of proteins and peptides. These oligomeric assemblies are important for at least two reasons. First, it is now believed that such forms, rather than mature fibrils, may be the cytotoxic agents responsible for some amyloid-associated disorders like Alzheimer's and Parkinson's diseases. Second, it has been proposed that these structures may be intimately involved in the amyloid fibril assembly mechanism, both in amyloid nucleation and fibril elongation. It is clear that an understanding of the driving forces involved in the formation of these organized assemblies rich in beta-sheet structure and of the kinetics and molecular features of the overall process of protein fibrillogenesis is required for the identification of therapeutic strategies to prevent or cure the severe diseases associated with amyloidosis. Here, we will be using apomyoglobin (apoMb, myoglobin without the heme) variants and fragments produced by >>>Timescale
24 monthsNational and international background
Amyloid and amyloid-related diseases result from the deposition of normally soluble proteins into insoluble plaques. Currently, more than 20 proteins are known to be associated with human amyloid diseases [1-6]. In addition, a number of other proteins and peptides with no known disease state have been shown to be capable of producing amyloid-like material [7,8]. Even though the native structures of the known amyloidogenic proteins vary widely, the fibrils they produce exhibit a common cross-beta structure giving rise to a characteristic X-ray fibre diffraction pattern [9-11]. These structural features, together with other assays, including the binding of thioflavin-T (ThT) and the demonstration of red-green birefringence in the presence of Congo red, are normally used to classify fibrillar deposits as amyloid material [10]. The observation that many proteins, even if not all, can assemble into a common cross-beta fibrillar architecture, regardless of their initial structure, suggests that amyloid may form by a common mechanism [12-16].Considering the generic nature of amyloid structure and the mechanism of its formation, even among proteins unrelated to amyloid diseases [1,7,8,16], nowadays there is a common belief that the fundamentals of protein misfolding and aggregation can be studied with model proteins, not necessarily linked to an amyloid disease [1,16]. For this reason, in this Project we aim to use apomyoglobin (apoMb) as a model protein for >>>
