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Inhibition of serum amyloid A protein amyloid formation

100%

Sosnowska M., Jankowska E.

Acta Neurobiologiae Experimentalis

2013

tom 73

nr 1

The acute-phase protein serum amyloid A (SAA) is present in the bloodstream at the concentration below 1 µM under physiological conditions, but its level increases significantly during the acute-phase response following infection or inflammatory condition. A consequence of the long-term elevated SAA concentration is deposition of normally soluble serum amyloid A in the form of insoluble fibrils, impairing tissue structure and function. These deposits cause development of a secondary type amyloidosis, called amyloid A protein (AA) amyloidosis, which results in a death of thousands of people per annum around the world. The ability of SAA to form amyloids seems to be connected with the N-terminal portion of the molecule. The capacity of the synthetic peptides derived from the N-terminal sequence of human or mice SAA to form fibrils in vitro proves that the most amyloidogenic region is embedded within the protein’s first 15 amino acids. We decided therefore to use peptides consisting of 11–15 amino acids and the sequence derived from the N-terminus of the parent aggregating protein as a research tool for investigation of the molecular recognition and self-assembly mechanisms that promote the formation of SAA amyloid fibrils deposits. In this study, we tested the hypothesis that non-aggregating very short peptides derived from SAA sequence would interact with the analogous region in the protein molecule or its aggregation-prone N-terminal fragment, and block its assembly into oligomers and amyloid fibrils. We designed and synthesized a peptide with the sequence 1RSFFS5, derived from the human SAA primary structure, and then tested it as a potential inhibitor of the aggregation process of SAA protein. The hypothesis about the role of aromatic interactions in amyloid fibril formation led us to test another peptide: 17LVFF20, which is derived from the sequence of Aβ. We tested propensity of the N-terminal segment (1–15) of mice SAA for amyloid fibrils formation, incubating it either alone or together with the potential inhibitors. Thioflavin T (ThT) fluorescence test was used to detect amyloid fibrils formation. These tests confirmed that the designed peptides are able to diminish propensity of the aggregation-prone SAA peptides to form amyloid fibrils. There are currently no effective medical treatment of diseases associated with the systemic amyloidosis. We believe that results of the presented project open up new possibilities in designing compounds that are able to prevent formation of amyloid deposits and could be a starting point for the design of peptidomimetic molecules more suitable as potential drugs. The work was supported by grant NCN nr 2011/03/N/NZ5/01460 and grant BMN No 538-8440-1042-12.

3D domain swapping, protein oligomerization, and amyloid formation

100%

Jaskolski M.

Acta Biochimica Polonica

2001

tom 48

nr 4

In 3D domain swapping, first described by Eisenberg, a structural element of a monomeric protein is replaced by the same element from another subunit. This process requires partial unfolding of the closed monomers that is then followed by adhesion and reconstruction of the original fold but from elements contributed by different subunits. If the interactions are reciprocal, a closed-ended dimer will be formed, but the same phenomenon has been suggested as a mechanism for the formation of open-ended polymers as well, such as those believed to exist in amyloid fibrils. There has been a rapid progress in the study of 3D domain swapping. Oligomers higher than dimers have been found, the monomer-dimer equilibrium could be controlled by mutations in the hinge element of the chain, a single protein has been shown to form more than one domain-swapped structure, and recently, the possibility of simultaneous exchange of two structural domains by a single molecule has been demonstrated. This last discovery has an important bearing on the possibility that 3D domain swapping might be indeed an amyloidogenic mechanism. Along the same lines is the discovery that a protein of proven amyloidogenic properties, human cystatin C, is capable of 3D domain swapping that leads to oligomerization. The structure of domain- swapped human cystatin C dimers explains why a naturally occurring mutant of this protein has a much higher propensity for aggregation, and also suggests how this same mechanism of 3D domain swapping could lead to an open-ended polymer that would be consistent with the cross-β structure, which is believed to be at the heart of the molecular architecture of amyloid fibrils.

Ograniczanie wyników

1 Acta Biochimica Polonica

1 Acta Neurobiologiae Experimentalis

1 Jankowska E.

1 Jaskolski M.

1 Sosnowska M.

1 2013

1 2001

Wyniki wyszukiwania

Inhibition of serum amyloid A protein amyloid formation

3D domain swapping, protein oligomerization, and amyloid formation