“…Intrinsically disordered proteins and protein regions (IDPs/IDRs) lack stable 3D structure in their functional state that confers a multitude of functional advantages [ 6 ], utilized in the diverse roles of IDPs in important biological processes [ 7 , 8 ].…”
Histone lysine methyltransferases (HKMTs), catalyze mono-, di- and trimethylation of lysine residues, resulting in a regulatory pattern that controls gene expression. Their involvement in many different cellular processes and diseases makes HKMTs an intensively studied protein group, but scientific interest so far has been concentrated mostly on their catalytic domains. In this work we set out to analyze the structural heterogeneity of human HKMTs and found that many contain long intrinsically disordered regions (IDRs) that are conserved through vertebrate species. Our predictions show that these IDRs contain several linear motifs and conserved putative binding sites that harbor cancer-related SNPs. Although there are only limited data available in the literature, some of the predicted binding regions overlap with interacting segments identified experimentally. The importance of a disordered binding site is illustrated through the example of the ternary complex between MLL1, menin and LEDGF/p75. Our suggestion is that intrinsic protein disorder plays an as yet unrecognized role in epigenetic regulation, which needs to be further elucidated through structural and functional studies aimed specifically at the disordered regions of HKMTs.Reviewers: This article was reviewed by Arne Elofsson and Piotr Zielenkiewicz.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-016-0129-2) contains supplementary material, which is available to authorized users.
“…Intrinsically disordered proteins and protein regions (IDPs/IDRs) lack stable 3D structure in their functional state that confers a multitude of functional advantages [ 6 ], utilized in the diverse roles of IDPs in important biological processes [ 7 , 8 ].…”
Histone lysine methyltransferases (HKMTs), catalyze mono-, di- and trimethylation of lysine residues, resulting in a regulatory pattern that controls gene expression. Their involvement in many different cellular processes and diseases makes HKMTs an intensively studied protein group, but scientific interest so far has been concentrated mostly on their catalytic domains. In this work we set out to analyze the structural heterogeneity of human HKMTs and found that many contain long intrinsically disordered regions (IDRs) that are conserved through vertebrate species. Our predictions show that these IDRs contain several linear motifs and conserved putative binding sites that harbor cancer-related SNPs. Although there are only limited data available in the literature, some of the predicted binding regions overlap with interacting segments identified experimentally. The importance of a disordered binding site is illustrated through the example of the ternary complex between MLL1, menin and LEDGF/p75. Our suggestion is that intrinsic protein disorder plays an as yet unrecognized role in epigenetic regulation, which needs to be further elucidated through structural and functional studies aimed specifically at the disordered regions of HKMTs.Reviewers: This article was reviewed by Arne Elofsson and Piotr Zielenkiewicz.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-016-0129-2) contains supplementary material, which is available to authorized users.
“…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.
“…Not surprisingly, IDRs are often located at the protein N- or C-terminus and act as interaction hubs in protein–protein networks [ 3 , 4 ]. This feature is instrumental to IDP/IDR involvement in crucial physiological processes, such as transcription, translation, and cell cycle regulation [ 2 , 5 , 6 , 7 ], and underlies the relationships between IDPs/IDRs and diseases (cancer, inflammation, or neurodegeneration) [ 8 , 9 ]. A central challenge for structural biology is understanding how sequence and sequence composition encode structural disorder.…”
The abundance of intrinsic disorder in the protein realm and its role in a variety of physiological and pathological cellular events have strengthened the interest of the scientific community in understanding the structural and dynamical properties of intrinsically disordered proteins (IDPs) and regions (IDRs). Attempts at rationalizing the general principles underlying both conformational properties and transitions of IDPs/IDRs must consider the abundance of charged residues (Asp, Glu, Lys, and Arg) that typifies these proteins, rendering them assimilable to polyampholytes or polyelectrolytes. Their conformation strongly depends on both the charge density and distribution along the sequence (i.e., charge decoration) as highlighted by recent experimental and theoretical studies that have introduced novel descriptors. Published experimental data are revisited herein in the frame of this formalism, in a new and possibly unitary perspective. The physicochemical properties most directly affected by charge density and distribution are compaction and solubility, which can be described in a relatively simplified way by tools of polymer physics. Dissecting factors controlling such properties could contribute to better understanding complex biological phenomena, such as fibrillation and phase separation. Furthermore, this knowledge is expected to have enormous practical implications for the design, synthesis, and exploitation of bio-derived materials and the control of natural biological processes.
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