Regulation of Functional Protein Aggregation by Multiple Factors: Implications for the Amyloidogenic Behavior of the CAP Superfamily Proteins

Abstract

The idea that amyloid fibrils and other types of protein aggregates are toxic for cells has been challenged by the discovery of a variety of functional aggregates. However, an identification of crucial differences between pathological and functional aggregation remains to be explored. Functional protein aggregation is often reversible by nature in order to respond properly to changing physiological conditions of the cell. In addition, increasing evidence indicates that fast fibril growth is a feature of functional amyloids, providing protection against the long-term existence of potentially toxic oligomeric intermediates. It is becoming clear that functional protein aggregation is a complexly organized process that can be mediated by a multitude of biomolecular factors. In this overview, we discuss the roles of diverse biomolecules, such as lipids/membranes, glycosaminoglycans, nucleic acids and metal ions, in regulating functional protein aggregation. Our studies on the protein GAPR-1 revealed that several of these factors influence the amyloidogenic properties of this protein. These observations suggest that GAPR-1, as well as the cysteine-rich secretory proteins, antigen 5 and pathogenesis-related proteins group 1 (CAP) superfamily of proteins that it belongs to, require the assembly into an amyloid state to exert several of their functions. A better understanding of functional aggregate formation may also help in the prevention and treatment of amyloid-related diseases.

Characterization of different oligomeric forms of CRISP2 in the perinuclear theca versus the fibrous tail structures of boar spermatozoa†

“…It is possible that a Zn 2+ interaction within CRISP2 and between CRISP2 or other proteins, is involved in the formation of reduction insensitive CRISP2 oligomers in the sperm tail. Moreover, we have demonstrated with other CAP family proteins that Zn 2+ can result in the formation of amyloid oligomeric structures in vitro that depend on the CAP domain [31,32]. The involvement of Zn 2+ in establishing specific features of the sperm tail during epididymal sperm maturation has been reported previously [68,69].…”

“…Of specific interest in this context is the property of CAP proteins such as CRISP2 (and other CRISP proteins) to form protein oligomers [31]. While little is known regarding this oligomer formation, the CAP domain of CRISP proteins may enable this [32], and the cysteine rich region of the protein may also be involved in protein aggregate formation in a redox sensitive manner [33][34][35]. Despite these intriguing leads, the involvement of CRISP2 in the diverse insoluble condensed protein structures in spermatozoa has not been addressed biochemically.…”

Cell Death via Lipid Peroxidation and Protein Aggregation Diseases

“…Type-B* (toxic) oligomers disrupt lipid bilayers more strongly than type A* (non-toxic) oligomers [ 42 ]. Amyloid-like aggregate formation is regulated by various factors, including lipids [ 43 ]. One of the therapeutic targets of neuropathy is the interaction between lipids and aggregated proteins [ 44 ].…”

Genome-Wide Characterization and Expression Analysis of Pathogenesis-Related 1 (PR-1) Gene Family in Tea Plant (Camellia sinensis (L.) O. Kuntze) in Response to Blister-Blight Disease Stress

“…PR-1 proteins 2 of 16 are related to cysteine-rich secretory proteins, the core regions of which are relatively conservative in various species [9]. The existence of a PR-1-like domain helps to deal with the stress of an adverse environment and improves the stability of PR-1-like proteins [10]. The CAP-derived peptide 1 (CAPE1, consensus motif PxGNxxxxxPY) has been found in the PR-1-like domain, which is related to stress signaling and conserved between the monocots and dicots [11].…”