DisoLipPred: accurate prediction of disordered lipid-binding residues in protein sequences with deep recurrent networks and transfer learning

Recurrent Network ◽

Lipid Binding ◽

Supplementary Information ◽

Cellular Functions ◽

Independent Test Dataset ◽

Binding Residues

Abstract Motivation Intrinsically disordered protein regions interact with proteins, nucleic acids and lipids. Regions that bind lipids are implicated in a wide spectrum of cellular functions and several human diseases. Motivated by the growing amount of experimental data for these interactions and lack of tools that can predict them from the protein sequence, we develop DisoLipPred, the first predictor of the disordered lipid-binding residues (DLBRs). Results DisoLipPred relies on a deep bidirectional recurrent network that implements three innovative features: transfer learning, bypass module that sidesteps predictions for putative structured residues, and expanded inputs that cover physiochemical properties associated with the protein–lipid interactions. Ablation analysis shows that these features drive predictive quality of DisoLipPred. Tests on an independent test dataset and the yeast proteome reveal that DisoLipPred generates accurate results and that none of the related existing tools can be used to indirectly identify DLBR. We also show that DisoLipPred’s predictions complement the results generated by predictors of the transmembrane regions. Altogether, we conclude that DisoLipPred provides high-quality predictions of DLBRs that complement the currently available methods. Availability and implementation DisoLipPred’s webserver is available at http://biomine.cs.vcu.edu/servers/DisoLipPred/. Supplementary information Supplementary data are available at Bioinformatics online.

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

Bioinformatics ◽

10.1093/bioinformatics/btz691 ◽

2019 ◽

Cited By ~ 2

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 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.

The Role of Post-Translational Modifications in the Phase Transitions of Intrinsically Disordered Proteins

International Journal of Molecular Sciences ◽

10.3390/ijms20215501 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5501 ◽

Cited By ~ 26

Author(s):

Izzy Owen ◽

Frank Shewmaker

Keyword(s):

Intrinsically Disordered Proteins ◽

Disordered Proteins ◽

Cellular Functions ◽

Post Translational Modifications ◽

Intrinsically Disordered Regions ◽

Genomics And Proteomics ◽

Eukaryotic Proteomes

Advances in genomics and proteomics have revealed eukaryotic proteomes to be highly abundant in intrinsically disordered proteins that are susceptible to diverse post-translational modifications. Intrinsically disordered regions are critical to the liquid–liquid phase separation that facilitates specialized cellular functions. Here, we discuss how post-translational modifications of intrinsically disordered protein segments can regulate the molecular condensation of macromolecules into functional phase-separated complexes.

A molecular recognition feature mediates ribosome-induced SRP-receptor assembly during protein targeting

The Journal of Cell Biology ◽

10.1083/jcb.201901001 ◽

2019 ◽

Vol 218 (10) ◽

pp. 3307-3319 ◽

Cited By ~ 2

Author(s):

Yu-Hsien Hwang Fu ◽

Sowmya Chandrasekar ◽

Jae Ho Lee ◽

Shu-ou Shan

Keyword(s):

Molecular Recognition ◽

Protein Targeting ◽

Signal Recognition Particle ◽

Signal Recognition ◽

Cellular Functions ◽

Disordered Protein ◽

Linker Domain ◽

Receptor Assembly

Molecular recognition features (MoRFs) provide interaction motifs in intrinsically disordered protein regions to mediate diverse cellular functions. Here we report that a MoRF element, located in the disordered linker domain of the mammalian signal recognition particle (SRP) receptor and conserved among eukaryotes, plays an essential role in sensing the ribosome during cotranslational protein targeting to the endoplasmic reticulum. Loss of the MoRF in the SRP receptor (SR) largely abolishes the ability of the ribosome to activate SRP-SR assembly and impairs cotranslational protein targeting. These results demonstrate a novel role for MoRF elements and provide a mechanism for the ribosome-induced activation of the mammalian SRP pathway. Kinetic analyses and comparison with the bacterial SRP further suggest that the SR MoRF functionally replaces the essential GNRA tetraloop in the bacterial SRP RNA, providing an example for the replacement of RNA function by proteins during the evolution of ancient ribonucleoprotein particles.

The Unconventional Self-Cleavage of Selenoprotein K

10.1101/2021.05.15.444318 ◽

2021 ◽

Author(s):

Rujin Cheng ◽

Jun Liu ◽

Martin Forstner ◽

George Woodward ◽

Elmer Heppard ◽

...

Keyword(s):

Cellular Functions ◽

Peptide Bonds ◽

Disordered Protein ◽

Catalytic Function ◽

Protein Partners ◽

Selenoprotein K

Through known association with other proteins, human selenoprotein K (selenok) is currently implicated in the palmitoylation of proteins, degradation of misfolded proteins, innate immune response, and the life cycle of SARS-CoV-2 virus. However, neither the catalytic function of selenok's selenocysteine (Sec), which, curiously, resides in an intrinsically disordered protein segment nor selenok's specific role in these pathways are known to date. This report casts these questions in a new light as it describes that selenok is able -both in vitro and in vivo- to cleave some of its own peptide bonds. The cleavages not only release selenok segments that contain its reactive Sec, but as the specific cleavage sites were identified, they proved to cluster tightly near sites through which selenok interacts with protein partners. Furthermore, it is shown that selenok's cleavage activity is neither restricted to itself nor promiscuous but selectively extends to at least one of its protein partners. Together, selenok's cleavage ability and its features have all hallmarks of a regulatory mechanism that could play a central role in selenok's associations with other proteins and its cellular functions overall.

The interactome of multifunctional HAX1 protein suggests its role in the regulation of energy metabolism, de-aggregation, cytoskeleton organization and RNA-processing

Bioscience Reports ◽

10.1042/bsr20203094 ◽

2020 ◽

Vol 40 (11) ◽

Cited By ~ 1

Author(s):

Maciej Wakula ◽

Anna Balcerak ◽

Tymon Rubel ◽

Mateusz Chmielarczyk ◽

Ryszard Konopinski ◽

...

Keyword(s):

Cellular Response ◽

Wide Spectrum ◽

Multifunctional Protein ◽

Cytoskeleton Organization ◽

Cellular Processes ◽

Disordered Protein ◽

Protein Partners ◽

Protein Interactome

Abstract HCLS1-associated protein X-1 (HAX1) is a multifunctional protein involved in many cellular processes, including apoptosis, cell migration and calcium homeostasis, but its mode of action still remains obscure. Multiple HAX1 protein partners have been identified, but they are involved in many distinct pathways, form different complexes and do not constitute a coherent group. By characterizing HAX1 protein interactome using targeted approach, we attempt to explain HAX1 multiple functions and its role in the cell. Presented analyses indicate that HAX1 interacts weakly with a wide spectrum of proteins and its interactome tends to be cell-specific, which conforms to a profile of intrinsically disordered protein (IDP). Moreover, we have identified a mitochondrial subset of HAX1 protein partners and preliminarily characterized its involvement in the cellular response to oxidative stress and aggregation.

Rapid Identification of Secondary Structure and Binding Site Residues in an Intrinsically Disordered Protein Segment

Frontiers in Genetics ◽

10.3389/fgene.2021.755292 ◽

2021 ◽

Vol 12 ◽

Author(s):

Soumyanetra Chandra ◽

Gopinath Chattopadhyay ◽

Raghavan Varadarajan

Keyword(s):

Rapid Identification ◽

Relative Reduction ◽

Toxin Binding ◽

Disordered Protein ◽

Yeast Surface ◽

Binding Residues ◽

Endoribonuclease Activity

Mycobacterium tuberculosis harbours nine toxin-antitoxin (TA) systems of the MazEF family. MazEF TA modules are of immense importance due to the perceived role of the MazF toxin in M. tuberculosis persistence and disease. The MazE antitoxin has a disordered C-terminal domain that binds the toxin, MazF and neutralizes its endoribonuclease activity. However, the structure of most MazEF TA complexes remains unsolved till date, obscuring structural and functional information about the antitoxins. We present a facile method to identify toxin binding residues on the disordered antitoxin. Charged residue scanning mutagenesis was used to screen a yeast surface displayed MazE6 antitoxin library against its purified cognate partner, the MazF6 toxin. Binding residues were deciphered by probing the relative reduction in binding to the ligand by flow cytometry. We have used this to identify putative antitoxin interface residues and local structure attained by the antitoxin upon interaction in the MazEF6 TA system and the same methodology is readily applicable to other intrinsically disordered protein regions.

Reading the phosphorylation code: binding of the 14-3-3 protein to multivalent client phosphoproteins

Biochemical Journal ◽

10.1042/bcj20200084 ◽

2020 ◽

Vol 477 (7) ◽

pp. 1219-1225 ◽

Cited By ~ 4

Author(s):

Nikolai N. Sluchanko

Keyword(s):

Protein Function ◽

Structural Basis ◽

Major Protein ◽

Post Translational Modifications ◽

Protein Protein Interaction ◽

Biochemical Journal ◽

Multiple Binding ◽

And Control

Many major protein–protein interaction networks are maintained by ‘hub’ proteins with multiple binding partners, where interactions are often facilitated by intrinsically disordered protein regions that undergo post-translational modifications, such as phosphorylation. Phosphorylation can directly affect protein function and control recognition by proteins that ‘read’ the phosphorylation code, re-wiring the interactome. The eukaryotic 14-3-3 proteins recognizing multiple phosphoproteins nicely exemplify these concepts. Although recent studies established the biochemical and structural basis for the interaction of the 14-3-3 dimers with several phosphorylated clients, understanding their assembly with partners phosphorylated at multiple sites represents a challenge. Suboptimal sequence context around the phosphorylated residue may reduce binding affinity, resulting in quantitative differences for distinct phosphorylation sites, making hierarchy and priority in their binding rather uncertain. Recently, Stevers et al. [Biochemical Journal (2017) 474: 1273–1287] undertook a remarkable attempt to untangle the mechanism of 14-3-3 dimer binding to leucine-rich repeat kinase 2 (LRRK2) that contains multiple candidate 14-3-3-binding sites and is mutated in Parkinson's disease. By using the protein-peptide binding approach, the authors systematically analyzed affinities for a set of LRRK2 phosphopeptides, alone or in combination, to a 14-3-3 protein and determined crystal structures for 14-3-3 complexes with selected phosphopeptides. This study addresses a long-standing question in the 14-3-3 biology, unearthing a range of important details that are relevant for understanding binding mechanisms of other polyvalent proteins.

Self-Assembling Micelles Based on an Intrinsically Disordered Protein Domain

10.26434/chemrxiv.7157507 ◽

2018 ◽

Author(s):

Sarah Klass ◽

Matthew J. Smith ◽

Tahoe Fiala ◽

Jessica Lee ◽

Anthony Omole ◽

...

Keyword(s):

Drug Delivery ◽

Fusion Proteins ◽

Organic Molecules ◽

Protein Domain ◽

Enzymatic Cleavage ◽

Disordered Protein ◽

Self Assembling ◽

Protein Tag

Herein, we describe a new series of fusion proteins that have been developed to self-assemble spontaneously into stable micelles that are 27 nm in diameter after enzymatic cleavage of a solubilizing protein tag. The sequences of the proteins are based on a human intrinsically disordered protein, which has been appended with a hydrophobic segment. The micelles were found to form across a broad range of pH, ionic strength, and temperature conditions, with critical micelle concentration (CMC) values below 1 µM being observed in some cases. The reported micelles were found to solubilize hydrophobic metal complexes and organic molecules, suggesting their potential suitability for catalysis and drug delivery applications.