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The structure-based design of a blocker of formation of amyloid fibers of the segment AADTWE in the mutant D38A of the protein transthyretin, which causes familial amyloidosis

Objective

Several neurodegenerative and systemic amyloid diseases are putatively caused by the formation of insoluble protein fibrils, which accumulate in human tissues and interfere with normal organ function. The amylome is the set of proteins that are capable of forming amyloid-like fibrils, as consequence of the self-aggregation of some segments.
The familial amyloidosis or FAP is a slowly progressive condition characterized by the buildup of abnormal deposits of transthyretin (TTR) in the body's organs. Most patients with FAP have early and severe impairment of the autonomious nervous system and also visual deterioration. A variant of TTR, presenting the D38A mutation, was detected in patients suffering from amyloidosis. Analysis performed by Eisenberg's team showed that the aspartic acid 38 is likely to be within a non self-aggregating segment in the native protein (ADDTWE). However, when this segment carries the mutation (AADTWE), it turns into a self-associating segment (not published). We hypothesize that this segment is the cause of the fibrillation of transthyretin for the D38A mutation and that disrupting packing of the fibril spine can hinder fibrillation.
The goal of this proposal is the structure-based design of a blocker of aggregation of amyloid fibers of the segment AADTWE in the mutant TTR[D38A]. We will develop two different strategies for designing putative blockers of the aggregation of TTR: the structure-based design of an all D-peptide inhibitor and the construct of a chimeric protein between aggregation-inhibitor HET-S globular domain and the self-aggregating segment AADTWE. We will have to check the established inhibition model by X-ray crystallography and NMR techniques. Finally, inhibitors can be purchased commercially for synthesis of the designed fibril blockers.
This project can be considered as a key in biomedical improvement, especially in neurodegenerative diseases, because it could bring us a way to stop the development of these illnesses.

Field of science

  • /engineering and technology/materials engineering/fibers
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/neurobiology

Call for proposal

FP7-PEOPLE-2011-IOF
See other projects for this call

Funding Scheme

MC-IOF - International Outgoing Fellowships (IOF)

Coordinator

EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Address
Raemistrasse 101
8092 Zuerich
Switzerland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 275 362,50
Administrative Contact
Roland Riek (Prof.)