Decoding the role of coiled-coil motifs in human prion-like proteins

Abstract

Prions are self-propagating proteins that cause fatal neurodegenerative diseases in humans. However, increasing evidence suggests that eukaryotic cells exploit prion conformational conversion for functional purposes. A recent study delineated a group of twenty prion-like proteins in humans, characterized by the presence of low-complexity glutamine-rich sequences with overlapping coiled-coil (CCs) motifs. This is the case of Mediator complex subunit 15 (MED15), which is overexpressed in a wide range of human cancers. Biophysical studies demonstrated that the prion-like domain (PrLD) of MED15 forms homodimers in solution, sustained by CCs interactions. Furthermore, the same coiled-coil (CC) region plays a crucial role in the PrLD structural transition to a transmissible β-sheet amyloid state. In this review, we discuss the role of CCs motifs and their contribution to amyloid transitions in human prion-like domains (PrLDs), while providing a comprehensive overview of six predicted human prion-like proteins involved in transcription, gene expression, or DNA damage response and associated with human disease, whose PrLDs contain or overlap with CCs sequences. Finally, we try to rationalize how these molecular signatures might relate to both their function and involvement in disease.

Functional Classification of Fusion Proteins in Sarcoma

“…The ability of PrLDs to facilitate the recruitment of chromatin remodeling complexes, as demonstrated in Ewing sarcoma, could be applicable to other sarcoma types. For instance, similar mechanisms may occur in other FET-fused sarcomas or MAML3-or NCOA2-fused sarcoma, which also contain PrLD domains [134]. Similarly, the SS18 low-complexity QPGY domain, conserved in the SS18::SSX chimeric protein in synovial sarcoma, enables the recruitment of BRG1 into LLPS [135].…”

Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease

“…In these cellular models, the C -terminus facilitates PFFs internalization by interacting with cell surface receptors [ 117 , 177 , 178 ]. Accordingly, and as for human prion proteins [ 179 , 180 ], α-Syn fibrils formed under different solution conditions share a common cross-β fold, but exhibit different conformation, seeding activity, neurotoxicity, and spreading in cells and when they are inoculated in rat brains [ 177 , 181 , 182 , 183 , 184 , 185 ]. These diverse conformational assemblies are called strains ( Figure 4 C,D) and could explain the existence of different synucleinopathies with unique clinical features [ 182 , 186 , 187 ] as their different properties would induce particular lesion profiles and brain region dissemination [ 188 ].…”

A Review of Fifteen Years Developing Computational Tools to Study Protein Aggregation

“…The A3Dassisted redesign of this protein is shown in Figure 2. Other A3D applications included the study of the impact on the aggregation of pathogenic [37,57,58] and non-pathogenic protein variants [54,[59][60][61], the analysis of the binding of antibacterial proteins to membranes [62], the understanding of chaperone client recognition [63], and the assistance with neglected tropical disease vaccine development [64] or model viral protein evolution throughout the SARS-CoV-2 pandemic [65].…”

“…Since its release, pWaltz has been applied, coupled to different PrLD boundary prediction algorithms, to detect soft amyloid cores in yeast and human prion-like proteins [85,86], to identify the first bacterial prion [87] and prion candidates in the malaria parasite [88], to evaluate mutation impact on prion-like protein aggregation [89], to understand the aggregation of human prion-like proteins [90], or to describe the mechanism of Med15 and TBP aggregation from initial coiled-coil conformations [60,91].…”