scholarly journals Proteome-wide signatures of function in highly diverged intrinsically disordered regions

2019 ◽  
Author(s):  
Taraneh Zarin ◽  
Bob Strome ◽  
Alex N Nguyen Ba ◽  
Simon Alberti ◽  
Julie D Forman-Kay ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequences ◽  
Functional Annotations ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Molecular Features ◽  
Primary Amino ◽  
Function Relationship ◽  
Disordered Regions

AbstractIntrinsically disordered regions make up a large part of the proteome, but the sequence-to-function relationship in these regions is poorly understood, in part because the primary amino acid sequences of these regions are poorly conserved in alignments. Here we use an evolutionary approach to detect molecular features that are preserved in the amino acid sequences of orthologous intrinsically disordered regions. We find that most disordered regions contain multiple molecular features that are preserved, and we define these as “evolutionary signatures” of disordered regions. We demonstrate that intrinsically disordered regions with similar evolutionary signatures can rescue functionin vivo,and that groups of intrinsically disordered regions with similar evolutionary signatures are strongly enriched for functional annotations and phenotypes. We propose that evolutionary signatures can be used to predict function for many disordered regions from their amino acid sequences.

scholarly journals Proteome-wide signatures of function in highly diverged intrinsically disordered regions

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Taraneh Zarin ◽  
Bob Strome ◽  
Alex N Nguyen Ba ◽  
Simon Alberti ◽  
Julie D Forman-Kay ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequences ◽  
Functional Annotations ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Molecular Features ◽  
Primary Amino ◽  
Function Relationship ◽  
Disordered Regions

Intrinsically disordered regions make up a large part of the proteome, but the sequence-to-function relationship in these regions is poorly understood, in part because the primary amino acid sequences of these regions are poorly conserved in alignments. Here we use an evolutionary approach to detect molecular features that are preserved in the amino acid sequences of orthologous intrinsically disordered regions. We find that most disordered regions contain multiple molecular features that are preserved, and we define these as ‘evolutionary signatures’ of disordered regions. We demonstrate that intrinsically disordered regions with similar evolutionary signatures can rescue function in vivo, and that groups of intrinsically disordered regions with similar evolutionary signatures are strongly enriched for functional annotations and phenotypes. We propose that evolutionary signatures can be used to predict function for many disordered regions from their amino acid sequences.

Differential roles of two DDX17 isoforms in the formation of membraneless organelles

2020 ◽  
Vol 168 (1) ◽  
pp. 33-40
Author(s):  
Yuya Hirai ◽  
Eisuke Domae ◽  
Yoshihiro Yoshikawa ◽  
Keizo Tomonaga
Keyword(s):  
Amino Acid ◽  
Enzymatic Activity ◽  
Rna Helicase ◽  
Intracellular Distribution ◽  
Amino Acid Sequences ◽  
Nucleolar Localization ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Dead Box ◽  
Additional Amino Acid

Abstract The RNA helicase, DDX17 is a member of the DEAD-box protein family. DDX17 has two isoforms: p72 and p82. The p82 isoform has additional amino acid sequences called intrinsically disordered regions (IDRs), which are related to the formation of membraneless organelles (MLOs). Here, we reveal that p72 is mostly localized to the nucleoplasm, while p82 is localized to the nucleoplasm and nucleoli. Additionally, p82 exhibited slower intranuclear mobility than p72. Furthermore, the enzymatic mutants of both p72 and p82 accumulate into the stress granules. The enzymatic mutant of p82 abolishes nucleolar localization of p82. Our findings suggest the importance of IDRs and enzymatic activity of DEAD-box proteins in the intracellular distribution and formation of MLOs.

NOT THAT RIGID MIDGETS AND NOT SO FLEXIBLE GIANTS: ON THE ABUNDANCE AND ROLES OF INTRINSIC DISORDER IN SHORT AND LONG PROTEINS

2012 ◽  
Vol 20 (04) ◽  
pp. 471-511 ◽  
Author(s):  
MARK HOWELL ◽  
RYAN GREEN ◽  
ALEXIS KILLEEN ◽  
LAMAR WEDDERBURN ◽  
VINCENT PICASCIO ◽  
...  
Keyword(s):  
Amino Acid ◽  
Intrinsically Disordered Proteins ◽  
Biological Activities ◽  
Intrinsic Disorder ◽  
Amino Acid Sequences ◽  
Disordered Proteins ◽  
Biological Functions ◽  
Intrinsically Disordered ◽  
Eukaryotic Proteins ◽  
Disordered Regions

Intrinsically disordered proteins or proteins with disordered regions are very common in nature. These proteins have numerous biological functions which are complementary to the biological activities of traditional ordered proteins. A noticeable difference in the amino acid sequences encoding long and short disordered regions was found and this difference was used in the development of length-dependent predictors of intrinsic disorder. In this study, we analyze the scaling of intrinsic disorder in eukaryotic proteins and investigate the presence of length-dependent functions attributed to proteins containing long disordered regions.

scholarly journals Handcuffing intrinsically disordered regions in Mlh1-Pms1 disrupts mismatch repair

2021 ◽  
Author(s):  
Christopher M. Furman ◽  
Ting-Yi Wang ◽  
Qiuye Zhao ◽  
Kumar Yugandhar ◽  
Haiyuan Yu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Mismatch Repair ◽  
Cross Linking ◽  
Dna Mismatch ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
On Demand ◽  
Transient Loss ◽  
Disordered Regions

AbstractThe DNA mismatch repair (MMR) factor Mlh1-Pms1 contains long intrinsically disordered regions (IDRs). While essential for MMR, their exact functions remain elusive. We performed cross-linking mass spectrometry to identify the major interactions within the Mlh1-Pms1 heterodimer and used this information to insert FRB and FKBP dimerization domains into the IDRs of Mlh1 and Pms1. Yeast bearing these constructs were grown with rapamycin to induce dimerization. Strains containing FRB and FKBP domains in the Mlh1 IDR displayed complete MMR defects when grown with rapamycin, but removing rapamycin restored MMR functions. Furthermore, linking the Mlh1 and Pms1 IDRs through FRB-FKBP dimerization disrupted Mlh1-Pms1 binding to DNA, inappropriately activated Mlh1-Pms1, and caused MMR defects in vivo. We conclude that dynamic and coordinated rearrangements of the MLH IDRs regulate how the complex clamps DNA to catalyze MMR. The application of the FRB-FKBP dimerization system to interrogate in vivo functions of a critical repair complex will be useful for probing IDRs in diverse enzymes and to probe transient loss of MMR on demand.

scholarly journals Proteome-scale amino-acid resolution footprinting of protein-binding sites in the intrinsically disordered regions of the human proteome

2021 ◽  
Author(s):  
Caroline Benz ◽  
Muhammad Ali ◽  
Izabella Krystkowiak ◽  
Leandro Simonetti ◽  
Ahmed Sayadi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Human Proteome ◽  
Cell Physiology ◽  
Protein Protein Interactions ◽  
Linear Motif ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Wide Range ◽  
Disordered Regions

Specific protein-protein interactions are central to all processes that underlie cell physiology. Numerous studies using a wide range of experimental approaches have identified tens of thousands of human protein-protein interactions. However, many interactions remain to be discovered, and low affinity, conditional and cell type-specific interactions are likely to be disproportionately under-represented. Moreover, for most known protein-protein interactions the binding regions remain uncharacterized. We previously developed proteomic peptide phage display (ProP-PD), a method for simultaneous proteome-scale identification of short linear motif (SLiM)-mediated interactions and footprinting of the binding region with amino acid resolution. Here, we describe the second-generation human disorderome (HD2), an optimized ProP-PD library that tiles all disordered regions of the human proteome and allows the screening of ~1,000,000 overlapping peptides in a single binding assay. We define guidelines for how to process, filter and rank the results and provide PepTools, a toolkit for annotation and analysis of identified hits. We uncovered 2,161 interaction pairs for 35 known SLiM-binding domains and confirmed a subset of 38 interactions by biophysical or cell-based assays. Finally, we show how the amino acid resolution binding site information can be used to pinpoint functionally important disease mutations and phosphorylation events in intrinsically disordered regions of the human proteome. The HD2 ProP-PD library paired with PepTools represents a powerful pipeline for unbiased proteome-wide discovery of SLiM-based interactions.

scholarly journals Why do eukaryotic proteins contain more intrinsically disordered regions?

2018 ◽  
Author(s):  
Walter Basile ◽  
Marco Salvatore ◽  
Claudio Bassot ◽  
Arne Elofsson
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Intrinsic Disorder ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Significant Difference ◽  
Eukaryotic Proteins ◽  
The Difference ◽  
Almost All ◽  
Disordered Regions

AbstractIntrinsic disorder is much more abundant in eukaryotic than in prokaryotic proteins. However, the reason behind this is unclear. It has been proposed that the disordered regions are functionally important for regulation in eukaryotes, but it has also been proposed that the difference is a result of lower selective pressure in eukaryotes. Almost all studies intrinsic disorder is predicted from the amino acid sequence of a protein. Therefore, there should exist an underlying difference in the amino acid distributions between eukaryotic and prokaryotic proteins causing the predicted difference in intrinsic disorder. To obtain a better understanding of why eukaryotic proteins contain more intrinsically disordered regions we compare proteins from complete eukaryotic and prokaryotic proteomes.Here, we show that the difference in intrinsic disorder origin from differences in the linker regions. Eukaryotic proteins have more extended linker regions and, in particular, the eukaryotic linker regions are more disordered. The average eukaryotic protein is about 500 residues long; it contains 250 residues in linker regions, of which 80 are disordered. In comparison, prokaryotic proteins are about 350 residues long and only have 100-110 residues in linker regions, and less than 10 of these are intrinsically disordered.Further, we show that there is no systematic increase in the frequency of disorder-promoting residues in eukaryotic linker regions. Instead, the difference in frequency of only three amino acids seems to lie behind the difference. The most significant difference is that eukaryotic linkers contain about 9% serine, while prokaryotic linkers have roughly 6.5%. Eukaryotic linkers also contain about 2% more proline and 2-3% fewer isoleucine residues. The reason why primarily these amino acids vary in frequency is not apparent, but it cannot be excluded that the difference is serine is related to the increased need for regulation through phosphorylation and that the proline difference is related to increase of eukaryotic specific repeats.

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