An Easy Protocol for Evolutionary Analysis of Intrinsically Disordered Proteins

Nunez-Castilla, Janelle; Siltberg-Liberles, Jessica

doi:10.1007/978-1-0716-0524-0_7

Cited by 6 publications

(7 citation statements)

References 48 publications

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“…The three additional heatmaps display the same region of the alignment colored by property. The heatmap for Disorder propensity displays disordered (magenta) or ordered (purple) residues based on IUPRED prediction with cutoff = 0.4 [35,36,59]. Heatmaps for (1) Surface accessibility displays surface exposed (magenta) and buried (white) residues and (2) Secondary structure displays coil (orange) and secondary structure (helix: blue, strand: magenta) based on NetSurfP-2.0 predictions.…”

Section: Furin Cleavage Motif Role In Viral Entrymentioning

confidence: 99%

Dynamic, but Not Necessarily Disordered, Human-Virus Interactions Mediated through SLiMs in Viral Proteins

Elkhaligy

Balbin

Gonzalez

et al. 2021

Viruses

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Most viruses have small genomes that encode proteins needed to perform essential enzymatic functions. Across virus families, primary enzyme functions are under functional constraint; however, secondary functions mediated by exposed protein surfaces that promote interactions with the host proteins may be less constrained. Viruses often form transient interactions with host proteins through conformationally flexible interfaces. Exposed flexible amino acid residues are known to evolve rapidly suggesting that secondary functions may generate diverse interaction potentials between viruses within the same viral family. One mechanism of interaction is viral mimicry through short linear motifs (SLiMs) that act as functional signatures in host proteins. Viral SLiMs display specific patterns of adjacent amino acids that resemble their host SLiMs and may occur by chance numerous times in viral proteins due to mutational and selective processes. Through mimicry of SLiMs in the host cell proteome, viruses can interfere with the protein interaction network of the host and utilize the host-cell machinery to their benefit. The overlap between rapidly evolving protein regions and the location of functionally critical SLiMs suggest that these motifs and their functional potential may be rapidly rewired causing variation in pathogenicity, infectivity, and virulence of related viruses. The following review provides an overview of known viral SLiMs with select examples of their role in the life cycle of a virus, and a discussion of the structural properties of experimentally validated SLiMs highlighting that a large portion of known viral SLiMs are devoid of predicted intrinsic disorder based on the viral SLiMs from the ELM database.

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Section: Furin Cleavage Motif Role In Viral Entrymentioning

confidence: 99%

Dynamic, but Not Necessarily Disordered, Human-Virus Interactions Mediated through SLiMs in Viral Proteins

Elkhaligy

Balbin

Gonzalez

et al. 2021

Viruses

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“…As an example, MSAs are important tools in studying the function and evolutionary relationships of proteins. However, it has been suggested that disordered proteins are difficult to align because they rapidly evolve and experience more frequent indels [ 6 – 9 ]. Our goal was to compare and assess the quality of MSAs created from disordered sequences to these from ordered sequences using several different tools and datasets.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been observed that insertions and deletions (indels) occur more frequently in disordered regions, likely due to the lower selective pressure in these regions [ 5 ]. This combination of higher substitution rates and more frequent indels may indicate that some IDPs are undergoing rapid evolution, which could result in a lower sequence identity between orthologues [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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The difficulty of aligning intrinsically disordered protein sequences as assessed by conservation and phylogeny

2023

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Intrinsically disordered proteins (IDPs) are proteins that lack a stable 3D structure but maintain a biological function. It has been frequently suggested that IDPs are difficult to align because they tend to have fewer conserved residues compared to ordered proteins, but to our knowledge this has never been directly tested. To compare the alignments of ordered proteins to IDPs, their multiple sequence alignments (MSAs) were assessed using two different methods. The first compared the similarity between MSAs produced using the same sequences but created with Clustal Omega, MAFFT, and MUSCLE. The second assessed MSAs based on how well they recapitulated the species tree. These two methods measure the “correctness” of an MSA with two different approaches; the first method measures consistency while the second measures the underlying phylogenetic signal. Proteins that contained both regions of disorder and order were analyzed along with proteins that were fully disordered and fully ordered, using nucleotide, codon and peptide sequence alignments. We observed that IDPs had less similar MSAs than ordered proteins, which is most likely linked to the lower sequence conservation in IDPs. However, comparisons of tree distances found that trees from the ordered sequence MSAs were not significantly closer to the species tree than those inferred from disordered sequence MSAs. Our results show that it is correct to say that IDPs are difficult to align on the basis of MSA consistency, but that this does not equate with alignments being of poor quality when assessed by their ability to correctly infer a species tree.

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“…A previously described protocol was used as a foundation [56]. The complete code can be found on GitHub (https://github.com/LabWolfrum/Fritze_et_al.2023.git).…”

Section: Evolutionary Conservationmentioning

confidence: 99%

Pathogenic Variants in USH1G/SANS Alter Protein Interaction with Pre-RNA Processing Factors PRPF6 and PRPF31 of the Spliceosome

Fritze,

Stiehler,

Wolfrum

2023

IJMS

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Pre-mRNA splicing is an essential process orchestrated by the spliceosome, a dynamic complex assembled stepwise on pre-mRNA. We have previously identified that USH1G protein SANS regulates pre-mRNA splicing by mediating the intranuclear transfer of the spliceosomal U4/U6.U5 tri-snRNP complex. During this process, SANS interacts with the U4/U6 and U5 snRNP-specific proteins PRPF31 and PRPF6 and regulates splicing, which is disturbed by variants of USH1G/SANS causative for human Usher syndrome (USH), the most common form of hereditary deaf–blindness. Here, we aim to gain further insights into the molecular interaction of the splicing molecules PRPF31 and PRPF6 to the CENTn domain of SANS using fluorescence resonance energy transfer assays in cells and in silico deep learning-based protein structure predictions. This demonstrates that SANS directly binds via two distinct conserved regions of its CENTn to the two PRPFs. In addition, we provide evidence that these interactions occur sequentially and a conformational change of an intrinsically disordered region to a short α-helix of SANS CENTn2 is triggered by the binding of PRPF6. Furthermore, we find that pathogenic variants of USH1G/SANS perturb the binding of SANS to both PRPFs, implying a significance for the USH1G pathophysiology.

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An Easy Protocol for Evolutionary Analysis of Intrinsically Disordered Proteins

Cited by 6 publications

References 48 publications

Dynamic, but Not Necessarily Disordered, Human-Virus Interactions Mediated through SLiMs in Viral Proteins

Dynamic, but Not Necessarily Disordered, Human-Virus Interactions Mediated through SLiMs in Viral Proteins

The difficulty of aligning intrinsically disordered protein sequences as assessed by conservation and phylogeny

Pathogenic Variants in USH1G/SANS Alter Protein Interaction with Pre-RNA Processing Factors PRPF6 and PRPF31 of the Spliceosome

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