Self-assembly of protein aggregates in ageing disorders: the lens and cataract model

Abstract

Cataract, neurodegenerative disease, macular degeneration and pathologies of ageing are often characterized by the slow progressive destabilization of proteins and their self-assembly to amyloid-like fibrils and aggregates. During normal cell differentiation, protein self-assembly is well established as a dynamic mechanism for cytoskeletal organization. With the increased emphasis on ageing disorders, there is renewed interest in small-molecule regulators of protein self-assembly. Synthetic peptides, mini-chaperones, aptamers, ATP and pantethine reportedly regulate self-assembly mechanisms involving small stress proteins, represented by human αB-crystallin, and their targets. Small molecules are being considered for direct application as molecular therapeutics to protect against amyloid and protein aggregation disorders in ageing cells and tissues in vivo . The identification of specific interactive peptide sites for effective regulation of protein self-assembly is underway using conventional and innovative technologies. The quantification of the functional interactions between small stress proteins and their targets in vivo remains a top research priority. The quantitative parameters controlling protein–protein interactions in vivo need characterization to understand the fundamental biology of self-assembling systems in normal cells and disorders of ageing.

Sequence characteristics responsible for protein‐protein interactions in the intrinsically disordered regions of caseins, amelogenins, and small heat‐shock proteins

“…[71] Likewise, a HspB5 peptide containing the FYL sequence was an effective inhibitor of amyloid fibril formation by the Aβ peptide and α-synuclein. [72] When orthologues of human HSPB1 were examined (Supporting Information A Tables S6 and S7) the two HO-SLiMs identified were found to be relatively well conserved and all contained at least one HO-SLiM. Notwithstanding this, the group of human sHsps was much more diverse in all their compositional and sequence characteristics than the group of HSPB1 orthologues.…”

Congenital Cataract-Causing Mutation G129C in γC-Crystallin Promotes the Accumulation of Two Distinct Unfolding Intermediates That Form Highly Toxic Aggregates

“…Many efforts have been devoted in recent years to elucidate the molecular mechanism of cataract caused by mutations or environmental factors [3,[13][14][15][16][17][18][19][20][21][22]. The most widely understood mechanism is the disruption of crystallin solubility and/or stability directly by mutations/modifications or indirectly by changes in cellular homeostasis.…”

A novel dominant D109A CRYAB mutation in a family with myofibrillar myopathy affects αB-crystallin structure

“…Interestingly, the mutated residue studied herein (D109) is located in the HGKHEERQDE sequence, which is one of the most effective inhibitors of amyloid-beta (Aβ) fibril formation [47], [48], [49]. This motif is located not in the monomer-monomer interface but in the second row (2nd β-thread in β-sheet).…”

“…This is particularly important, as the distal parts of this sequence (i.e. : HEER and RQDE) were shown to enhance fibril formation of Aβ [47], [48], [49] As native CRYAB is protective against aggregation of lens crystallins in aging cataract, it could be speculated that D/A and D/H substitutions in position 109 diminish the native functional role of the whole HGKHEERQDE sequence [50]. These predictions were confirmed by immunostaining for CRYAB of the proband's biopsied muscle that showed the presence of large aggregate-like structures distributed not only at the fiber periphery but also within the fiber.…”