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Conformational Diseases: Structural Studies of Aggregation of Polyglutamine Proteins

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Protein misfolding and aggregation into insoluble amyloid deposits are often associated with neurodegenerative disorders. In particular, the polyglutamine (polyQ) diseases are inherited disorders triggered by the expansion of the polyQ tract over its physiological length in the involved protein. The molecular mechanism of aggregation from the native protein into amyloids involves several steps including protein misfolding, aggregation into oligomers, which seems to be the most toxic species, and, finally rearrangements into mature fibrils. In the present contribution, we review studies, integrating computational and experimental approaches, of polyQ proteins, as well as of the details of the complicate aggregation mechanisms in which aberrant form of polyQ proteins are involved. These aspects are of crucial relevance for a complete understanding of the onset of polyQ conformational diseases and can also shed light on putative therapeutic targets and future development of aggregation inhibitors.

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Keywords: 2 proline helix-breaker residues; 2-3 harpin; A amyloid peptide; AT-3(Q15); AT-3(Q64); AT-3(QHQ); AXH domain; Alzheimer's; Amyloid fibrils; Asn-rich sequences; CAG; CAG repeat diseases; CAT; EGCG (epigallocatechin-3-gallate); GABAergic medium spiny striatal neurons (MSN); GNNQQNY; Gln; Gln-repeats; HBP1; His-Gln-His sequence; K48-linked tetra-ubiquitin chains; MATLEKLMKAFESLKSF; Machado Joseph Disease; Molten oligomers; Monomeric polyglutamine; N-terminal Josephin domain; NMR; Nt17; OPLSAA/L force field; Optimized Potential for Effective Peptide (OPEP); Parkinson's; Protein Intermediate Resolution Model (PRIME); Q20; Q22 peptide; Q24; Q41 peptide; SCA1; Size Exclusion Chromatography (SEC); Sup34-N; TANGO algorithm confirms; Transmission Electron Microscopy (TEM); UV-CD spectroscopy; Ure2p; X-ray diffraction; aggregates; aggregating peptides; aggregation inhibitors; amyloids; antiparallel (AP) structures; arginine [R]; aspartate [D]; ataxin; ataxin-1 (AT-1); ataxin-3 (AT-3); ataxins; atrophin-1; chimeric chymotrypsin inhibitor 2 (CI2)-polyQ; chimeric proteins; circular dichroism; conformational disease; cryo-electron microscopy; de-ubiquitinating activity; electron microscopy; electron paramagnetic resonance; fluorescence resonance energy transfer; geldanamycin; glutamate [E]; heat shock transcription factor 1 (HSF1); histone acetyltransferase; huntingtin; huntingtin (Htt); hydrogen exchange; hydrogen-bonded amyloid core; isoenergetic fibrillar form; lysine [K]; mesoglobules; molecular dynamics simulations; mutational approaches; non-aggregating; non-amyloidogenic protein; p53; pathogenic threshold; peptide-rich micro-phases; polyGln tract; polyPro type II-like helix (PPIIlike); polyQ binding peptide 1 (QPBP1); polyQ disease; polyglutamine (polyQ) diseases; polyglutamine expansions; polyubiquitin chains; protein aggregation; protein intermediate resolution model (PRIME); protein misfolding; protofilaments; replica-exchange MD (REMD); sheet supramolecular structures; single molecule force-clamp spectroscopy; size-exclusion chromatography; super-oxide dismutase 1 (SOD1); synuclein; transmission electron microscopy; ubiquitin interacting motifs (UIMs)

Document Type: Research Article

Publication date: March 1, 2011

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