Promiscuity as a functional trait: intrinsically disordered regions as central players of interactomes

2013 ◽  
Vol 454 (3) ◽  
pp. 361-369 ◽  
Author(s):  
Alexander Cumberworth ◽  
Guillaume Lamour ◽  
M. Madan Babu ◽  
Jörg Gsponer
Keyword(s):  
Low Complexity ◽  
Functional Trait ◽  
Protein Interaction Networks ◽  
Altered Expression ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Linear Motifs ◽  
Eukaryotic Genomes ◽  
Molecular Recognition Features ◽  
Disordered Regions

Because of their pervasiveness in eukaryotic genomes and their unique properties, understanding the role that ID (intrinsically disordered) regions in proteins play in the interactome is essential for gaining a better understanding of the network. Especially critical in determining this role is their ability to bind more than one partner using the same region. Studies have revealed that proteins containing ID regions tend to take a central role in protein interaction networks; specifically, they act as hubs, interacting with multiple different partners across time and space, allowing for the co-ordination of many cellular activities. There appear to be three different modules within ID regions responsible for their functionally promiscuous behaviour: MoRFs (molecular recognition features), SLiMs (small linear motifs) and LCRs (low complexity regions). These regions allow for functionality such as engaging in the formation of dynamic heteromeric structures which can serve to increase local activity of an enzyme or store a collection of functionally related molecules for later use. However, the use of promiscuity does not come without a cost: a number of diseases that have been associated with ID-containing proteins seem to be caused by undesirable interactions occurring upon altered expression of the ID-containing protein.

scholarly journals A sequence-based computational method for prediction of MoRFs

RSC Advances ◽  
2017 ◽  
Vol 7 (31) ◽  
pp. 18937-18945 ◽  
Author(s):  
Yu Wang ◽  
Yanzhi Guo ◽  
Xuemei Pu ◽  
Menglong Li
Keyword(s):  
Molecular Recognition ◽  
Computational Method ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Partner Proteins ◽  
Molecular Recognition Features ◽  
Disordered Regions

Molecular recognition features (MoRFs) are relatively short segments (10–70 residues) within intrinsically disordered regions (IDRs) that can undergo disorder-to-order transitions during binding to partner proteins.

scholarly journals FOXP in Tetrapoda: Intrinsically Disordered Regions, Short Linear Motifs and their evolutionary significance

2017 ◽  
Vol 40 (1) ◽  
pp. 181-190 ◽  
Author(s):  
Lucas Henriques Viscardi ◽  
Luciana Tovo-Rodrigues ◽  
Pamela Paré ◽  
Nelson Jurandi Rosa Fagundes ◽  
Francisco Mauro Salzano ◽  
...  
Keyword(s):  
Evolutionary Significance ◽  
Short Linear Motifs ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Linear Motifs ◽  
Disordered Regions

scholarly journals Short linear motifs in intrinsically disordered regions modulate HOG signaling capacity

2018 ◽  
Vol 12 (1) ◽  
Author(s):  
Bob Strome ◽  
Ian Shenyen Hsu ◽  
Mitchell Li Cheong Man ◽  
Taraneh Zarin ◽  
Alex Nguyen Ba ◽  
...  
Keyword(s):  
Short Linear Motifs ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Linear Motifs ◽  
Disordered Regions

scholarly journals An in vitro reconstituted U1 snRNP allows the study of the disordered regions of the particle and the interactions with proteins and ligands

2021 ◽  
Author(s):  
Sébastien Campagne ◽  
Tebbe de Vries ◽  
Florian Malard ◽  
Pavel Afanasyev ◽  
Georg Dorn ◽  
...  
Keyword(s):  
Nmr Spectroscopy ◽  
Molecular Mechanisms ◽  
Low Complexity ◽  
Stem Loop ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
U1 Snrnp ◽  
Splicing Regulator ◽  
Disordered Regions

Abstract U1 small nuclear ribonucleoparticle (U1 snRNP) plays a central role during RNA processing. Previous structures of U1 snRNP revealed how the ribonucleoparticle is organized and recognizes the pre-mRNA substrate at the exon–intron junction. As with many other ribonucleoparticles involved in RNA metabolism, U1 snRNP contains extensions made of low complexity sequences. Here, we developed a protocol to reconstitute U1 snRNP in vitro using mostly full-length components in order to perform liquid-state NMR spectroscopy. The accuracy of the reconstitution was validated by probing the shape and structure of the particle by SANS and cryo-EM. Using an NMR spectroscopy-based approach, we probed, for the first time, the U1 snRNP tails at atomic detail and our results confirm their high degree of flexibility. We also monitored the labile interaction between the splicing factor PTBP1 and U1 snRNP and validated the U1 snRNA stem loop 4 as a binding site for the splicing regulator on the ribonucleoparticle. Altogether, we developed a method to probe the intrinsically disordered regions of U1 snRNP and map the interactions controlling splicing regulation. This approach could be used to get insights into the molecular mechanisms of alternative splicing and screen for potential RNA therapeutics.

scholarly journals Short Linear Motifs In Intrinsically Disordered Regions Modulate HOG Signaling Capacity

2017 ◽  
Author(s):  
Bob Strome ◽  
Ian Hsu ◽  
Mitchell Li Cheong Man ◽  
Taraneh Zarin ◽  
Alex Nguyen Ba ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Fluorescent Reporter ◽  
Short Linear Motifs ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Large Numbers ◽  
Evolutionarily Conserved ◽  
Linear Motifs ◽  
Functionally Diverse ◽  
Disordered Regions

AbstractThe effort to characterize intrinsically disordered regions of signaling proteins is rapidly expanding. An important class of disordered interaction modules are ubiquitous and functionally diverse elements known as short linear motifs (SLiMs). To further examine the role of SLiMs in signal transduction, we used a previously devised bioinformatics method to predict evolutionarily conserved SLiMs within a well-characterized pathway in S. cerevisiae. Using a single cell, reporter-based flow cytometry assay in conjunction with a fluorescent reporter driven by a pathway-specific promoter, we quantitatively assessed pathway output via systematic deletions of individual motifs. We found that, when deleted, 34% (10/29) of predicted SLiMs displayed a significant decrease in pathway output, providing evidence that these motifs play a role in signal transduction. In addition, we show that perturbations of parameters in a previously published stochastic model of HOG signaling could reproduce the quantitative effects of 4 out of 7 mutations in previously unknown SLiMs. Our study suggests that, even in well-characterized pathways, large numbers of functional elements remain undiscovered, and that challenges remain for application of systems biology models to interpret the effects of mutations in signalling pathways.One-sentence SummaryMutations of short conserved elements in disordered regions have quantitative effects on a model signaling pathway.

Identifying molecular recognition features in intrinsically disordered regions of proteins by transfer learning

2019 ◽  
Author(s):  
Jack Hanson ◽  
Thomas Litfin ◽  
Kuldip Paliwal ◽  
Yaoqi Zhou
Keyword(s):  
Molecular Recognition ◽  
Transfer Learning ◽  
Analytical Models ◽  
Superior Performance ◽  
Supplementary Information ◽  
Disorder Prediction ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Molecular Recognition Features ◽  
Disordered Regions

Abstract Motivation Protein intrinsic disorder describes the tendency of sequence residues to not fold into a rigid three-dimensional shape by themselves. However, some of these disordered regions can transition from disorder to order when interacting with another molecule in segments known as molecular recognition features (MoRFs). Previous analysis has shown that these MoRF regions are indirectly encoded within the prediction of residue disorder as low-confidence predictions [i.e. in a semi-disordered state P(D)≈0.5]. Thus, what has been learned for disorder prediction may be transferable to MoRF prediction. Transferring the internal characterization of protein disorder for the prediction of MoRF residues would allow us to take advantage of the large training set available for disorder prediction, enabling the training of larger analytical models than is currently feasible on the small number of currently available annotated MoRF proteins. In this paper, we propose a new method for MoRF prediction by transfer learning from the SPOT-Disorder2 ensemble models built for disorder prediction. Results We confirm that directly training on the MoRF set with a randomly initialized model yields substantially poorer performance on independent test sets than by using the transfer-learning-based method SPOT-MoRF, for both deep and simple networks. Its comparison to current state-of-the-art techniques reveals its superior performance in identifying MoRF binding regions in proteins across two independent testing sets, including our new dataset of >800 protein chains. These test chains share <30% sequence similarity to all training and validation proteins used in SPOT-Disorder2 and SPOT-MoRF, and provide a much-needed large-scale update on the performance of current MoRF predictors. The method is expected to be useful in locating functional disordered regions in proteins. Availability and implementation SPOT-MoRF and its data are available as a web server and as a standalone program at: http://sparks-lab.org/jack/server/SPOT-MoRF/index.php. Contact [email protected] or [email protected] Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals An intrinsically disordered motif regulates the interaction between the p47 adaptor and the p97 AAA+ ATPase

2020 ◽  
Vol 117 (42) ◽  
pp. 26226-26236
Author(s):  
Alexander E. Conicella ◽  
Rui Huang ◽  
Zev A. Ripstein ◽  
Ai Nguyen ◽  
Eric Wang ◽  
...  
Keyword(s):  
Lipid Membrane ◽  
Adenosine Diphosphate ◽  
Membrane Remodeling ◽  
Electron Cryomicroscopy ◽  
Aaa Atpase ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Structural Ensembles ◽  
Linear Motifs ◽  
Disordered Regions

VCP/p97, an enzyme critical to proteostasis, is regulated through interactions with protein adaptors targeting it to specific cellular tasks. One such adaptor, p47, forms a complex with p97 to direct lipid membrane remodeling. Here, we use NMR and other biophysical methods to study the structural dynamics of p47 and p47–p97 complexes. Disordered regions in p47 are shown to be critical in directing intra-p47 and p47–p97 interactions via a pair of previously unidentified linear motifs. One of these, an SHP domain, regulates p47 binding to p97 in a manner that depends on the nucleotide state of p97. NMR and electron cryomicroscopy data have been used as restraints in molecular dynamics trajectories to develop structural ensembles for p47–p97 complexes in adenosine diphosphate (ADP)- and adenosine triphosphate (ATP)-bound conformations, highlighting differences in interactions in the two states. Our study establishes the importance of intrinsically disordered regions in p47 for the formation of functional p47–p97 complexes.

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