“…These features confer to the oligomers the ability to engage in aberrant interactions with multiple key cellular proteins (153,154). The proteins targeted by toxic aggregates are often themselves metastable (155,156); they are typically enriched in intrinsically unstructured regions and sequences of low amino acid complexity, characteristic features of many RNAbinding proteins (154)(155)(156)(157). Toxic protein aggregation interferes with nucleocytoplasmic transport of RNA and protein and generally impairs RNA homeostasis (156,158).…”
Most proteins must fold into unique three-dimensional structures to perform their biological functions. In the crowded cellular environment, newly synthesized proteins are at risk of misfolding and forming toxic aggregate species. To ensure efficient folding, different classes of molecular chaperones receive the nascent protein chain emerging from the ribosome and guide it along a productive folding pathway. Because proteins are structurally dynamic, constant surveillance of the proteome by an integrated network of chaperones and protein degradation machineries is required to maintain protein homeostasis (proteostasis). The capacity of this proteostasis network declines during aging, facilitating neurodegeneration and other chronic diseases associated with protein aggregation. Understanding the proteostasis network holds the promise of identifying targets for pharmacological intervention in these pathologies.
“…These features confer to the oligomers the ability to engage in aberrant interactions with multiple key cellular proteins (153,154). The proteins targeted by toxic aggregates are often themselves metastable (155,156); they are typically enriched in intrinsically unstructured regions and sequences of low amino acid complexity, characteristic features of many RNAbinding proteins (154)(155)(156)(157). Toxic protein aggregation interferes with nucleocytoplasmic transport of RNA and protein and generally impairs RNA homeostasis (156,158).…”
Most proteins must fold into unique three-dimensional structures to perform their biological functions. In the crowded cellular environment, newly synthesized proteins are at risk of misfolding and forming toxic aggregate species. To ensure efficient folding, different classes of molecular chaperones receive the nascent protein chain emerging from the ribosome and guide it along a productive folding pathway. Because proteins are structurally dynamic, constant surveillance of the proteome by an integrated network of chaperones and protein degradation machineries is required to maintain protein homeostasis (proteostasis). The capacity of this proteostasis network declines during aging, facilitating neurodegeneration and other chronic diseases associated with protein aggregation. Understanding the proteostasis network holds the promise of identifying targets for pharmacological intervention in these pathologies.
“…Not surprisingly, it has been reported that aggregates of IDPs are found in very high concentrations in plaques and brain deposits of patients with neurodegenerative diseases (Figure 9A). Similarly, mutations within IDRs that increase the aggregation propensity, such as those seen in the amyloid β-peptide, α-synuclein, and huntingtin, have been directly linked to diseases such as Alzheimer's, Parkinson's, and Huntington's diseases, respectively [7,19,24,86,87,148–153]. Figure 9.IDRs and disease.( A ) IDRs are found in plaques and cellular deposits of patients with neurodegenerative disease.…”
In the 1960s, Christian Anfinsen postulated that the unique three-dimensional structure of a protein is determined by its amino acid sequence. This work laid the foundation for the sequence–structure–function paradigm, which states that the sequence of a protein determines its structure, and structure determines function. However, a class of polypeptide segments called intrinsically disordered regions does not conform to this postulate. In this review, I will first describe established and emerging ideas about how disordered regions contribute to protein function. I will then discuss molecular principles by which regulatory mechanisms, such as alternative splicing and asymmetric localization of transcripts that encode disordered regions, can increase the functional versatility of proteins. Finally, I will discuss how disordered regions contribute to human disease and the emergence of cellular complexity during organismal evolution.
“…Many cellular RNAs associate with RNA-binding proteins to form ribonucleoprotein (RNP) complexes 105,106 . A large number of RNA binding proteins contain RGG/RG motif 107 or the related RGG/YGG motif 108 .…”
Section: G-quadruplexes and Trans-acting Proteinsmentioning
DNA guanine (G)-rich 4-stranded helical nucleic acid structures called G-quadruplexes (G4), have been extensively studied during the last decades. However, emerging evidence reveals that 5′- and 3′-untranslated regions (5′- and 3′-UTRs) as well as open reading frames (ORFs) contain putative RNA G-quadruplexes. These stable secondary structures play key roles in telomere homeostasis and RNA metabolism including pre-mRNA splicing, polyadenylation, mRNA targeting and translation. Interestingly, multiple RNA binding proteins such as nucleolin, FMRP, DHX36, and Aven were identified to bind RNA G-quadruplexes. Moreover, accumulating reports suggest that RNA G-quadruplexes regulate translation in cap-dependent and -independent manner. Herein, we discuss potential roles of RNA G-quadruplexes and associated trans-acting factors in the regulation of mRNA translation.
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