Cryoprotective activities of FK20, a human genome-derived intrinsically disordered peptide against cryosensitive enzymes without a stereospecific molecular interaction

Background Intrinsically disordered proteins (IDPs) have been shown to exhibit cryoprotective activity toward other cellular enzymes without any obvious conserved sequence motifs. This study investigated relationships between the physical properties of several human genome-derived IDPs and their cryoprotective activities. Methods Cryoprotective activity of three human-genome derived IDPs and their truncated peptides toward lactate dehydrogenase (LDH) and glutathione S-transferase (GST) was examined. After the shortest cryoprotective peptide was defined (named FK20), cryoprotective activity of all-D-enantiomeric isoform of FK20 (FK20-D) as well as a racemic mixture of FK20 and FK20-D was examined. In order to examine the lack of increase of thermal stability of the target enzyme, the CD spectra of GST and LDH in the presence of a racemic mixture of FK20 and FK20-D at varying temperatures were measured and used to estimate Tm. Results Cryoprotective activity of IDPs longer than 20 amino acids was nearly independent of the amino acid length. The shortest IDP-derived 20 amino acid length peptide with sufficient cryoprotective activity was developed from a series of TNFRSF11B fragments (named FK20). FK20, FK20-D, and an equimolar mixture of FK20 and FK20-D also showed similar cryoprotective activity toward LDH and GST. Tm of GST in the presence and absence of an equimolar mixture of FK20 and FK20-D are similar, suggesting that IDPs’ cryoprotection mechanism seems partly from a molecular shielding effect rather than a direct interaction with the target enzymes.

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Sequence Versus Composition: What Prescribes IDP Biophysical Properties?

Entropy ◽

10.3390/e21070654 ◽

2019 ◽

Vol 21 (7) ◽

pp. 654 ◽

Cited By ~ 2

Author(s):

Jiří Vymětal ◽

Jiří Vondrášek ◽

Klára Hlouchová

Keyword(s):

Amino Acid ◽

Secondary Structure ◽

Intrinsically Disordered Proteins ◽

Random Sequence ◽

Bioinformatic Analysis ◽

Globular Proteins ◽

Disordered Proteins ◽

Compositional Bias ◽

Intrinsically Disordered ◽

Sequence Versus

Intrinsically disordered proteins (IDPs) represent a distinct class of proteins and are distinguished from globular proteins by conformational plasticity, high evolvability and a broad functional repertoire. Some of their properties are reminiscent of early proteins, but their abundance in eukaryotes, functional properties and compositional bias suggest that IDPs appeared at later evolutionary stages. The spectrum of IDP properties and their determinants are still not well defined. This study compares rudimentary physicochemical properties of IDPs and globular proteins using bioinformatic analysis on the level of their native sequences and random sequence permutations, addressing the contributions of composition versus sequence as determinants of the properties. IDPs have, on average, lower predicted secondary structure contents and aggregation propensities and biased amino acid compositions. However, our study shows that IDPs exhibit a broad range of these properties. Induced fold IDPs exhibit very similar compositions and secondary structure/aggregation propensities to globular proteins, and can be distinguished from unfoldable IDPs based on analysis of these sequence properties. While amino acid composition seems to be a major determinant of aggregation and secondary structure propensities, sequence randomization does not result in dramatic changes to these properties, but for both IDPs and globular proteins seems to fine-tune the tradeoff between folding and aggregation.

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Analysis of Heterodimeric “Mutual Synergistic Folding”-Complexes

International Journal of Molecular Sciences ◽

10.3390/ijms20205136 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5136 ◽

Cited By ~ 3

Author(s):

Mentes ◽

Magyar ◽

Fichó ◽

Simon

Keyword(s):

Amino Acid ◽

Amino Acid Composition ◽

Acid Composition ◽

Intrinsically Disordered Proteins ◽

Driving Forces ◽

Disordered Proteins ◽

Subunit Interactions ◽

Amino Acid Compositions ◽

Intrinsically Disordered ◽

Β Sheet

Several intrinsically disordered proteins (IDPs) are capable to adopt stable structures without interacting with a folded partner. When the folding of all interacting partners happens at the same time, coupled with the interaction in a synergistic manner, the process is called Mutual Synergistic Folding (MSF). These complexes represent a discrete subset of IDPs. Recently, we collected information on their complexes and created the MFIB (Mutual Folding Induced by Binding) database. In a previous study, we compared homodimeric MSF complexes with homodimeric and monomeric globular proteins with similar amino acid sequence lengths. We concluded that MSF homodimers, compared to globular homodimeric proteins, have a greater solvent accessible main-chain surface area on the contact surface of the subunits, which becomes buried during dimerization. The main driving force of the folding is the mutual shielding of the water-accessible backbones, but the formation of further intermolecular interactions can also be relevant. In this paper, we will report analyses of heterodimeric MSF complexes. Our results indicate that the amino acid composition of the heterodimeric MSF monomer subunits slightly diverges from globular monomer proteins, while after dimerization, the amino acid composition of the overall MSF complexes becomes more similar to overall amino acid compositions of globular complexes. We found that inter-subunit interactions are strengthened, and additionally to the shielding of the solvent accessible backbone, other factors might play an important role in the stabilization of the heterodimeric structures, likewise energy gain resulting from the interaction of the two subunits with different amino acid compositions. We suggest that the shielding of the β-sheet backbones and the formation of a buried structural core along with the general strengthening of inter-subunit interactions together could be the driving forces of MSF protein structural ordering upon dimerization.

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Identifying short disorder-to-order binding regions in disordered proteins with a deep convolutional neural network method

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720019500045 ◽

2019 ◽

Vol 17 (01) ◽

pp. 1950004 ◽

Cited By ~ 2

Author(s):

Chun Fang ◽

Yoshitaka Moriwaki ◽

Aikui Tian ◽

Caihong Li ◽

Kentaro Shimizu

Keyword(s):

Neural Network ◽

Amino Acid ◽

Convolutional Neural Network ◽

Intrinsically Disordered Proteins ◽

Protein Sequences ◽

Interaction Network ◽

Deep Convolutional Neural Network ◽

Disordered Proteins ◽

Related Factors ◽

Intrinsically Disordered

Molecular recognition features (MoRFs) are key functional regions of intrinsically disordered proteins (IDPs), which play important roles in the molecular interaction network of cells and are implicated in many serious human diseases. Identifying MoRFs is essential for both functional studies of IDPs and drug design. This study adopts the cutting-edge machine learning method of artificial intelligence to develop a powerful model for improving MoRFs prediction. We proposed a method, named as en_DCNNMoRF (ensemble deep convolutional neural network-based MoRF predictor). It combines the outcomes of two independent deep convolutional neural network (DCNN) classifiers that take advantage of different features. The first, DCNNMoRF1, employs position-specific scoring matrix (PSSM) and 22 types of amino acid-related factors to describe protein sequences. The second, DCNNMoRF2, employs PSSM and 13 types of amino acid indexes to describe protein sequences. For both single classifiers, DCNN with a novel two-dimensional attention mechanism was adopted, and an average strategy was added to further process the output probabilities of each DCNN model. Finally, en_DCNNMoRF combined the two models by averaging their final scores. When compared with other well-known tools applied to the same datasets, the accuracy of the novel proposed method was comparable with that of state-of-the-art methods. The related web server can be accessed freely via http://vivace.bi.a.u-tokyo.ac.jp:8008/fang/en_MoRFs.php .

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Roles, Characteristics, and Analysis of Intrinsically Disordered Proteins: A Minireview

Life ◽

10.3390/life10120320 ◽

2020 ◽

Vol 10 (12) ◽

pp. 320

Author(s):

Frederik Lermyte

Keyword(s):

Amino Acid ◽

Amino Acid Sequence ◽

Neurological Disorders ◽

Intrinsically Disordered Proteins ◽

Intrinsic Disorder ◽

Disordered Proteins ◽

Dynamic Nature ◽

Intrinsically Disordered ◽

Unfolded State ◽

Underlying Causes

In recent years, there has been a growing understanding that a significant fraction of the eukaryotic proteome is intrinsically disordered, and that these conformationally dynamic proteins play a myriad of vital biological roles in both normal and pathological states. In this review, selected examples of intrinsically disordered proteins are highlighted, with particular attention for a few which are relevant in neurological disorders and in viral infection. Next, the underlying causes for intrinsic disorder are discussed, along with computational methods used to predict whether a given amino acid sequence is likely to adopt a folded or unfolded state in solution. Finally, biophysical methods for the analysis of intrinsically disordered proteins will be discussed, as well as the unique challenges they pose in this context due to their highly dynamic nature.

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Exclusively Heteronuclear13C-Detected Amino-Acid-Selective NMR Experiments for the Study of Intrinsically Disordered Proteins (IDPs)

ChemBioChem ◽

10.1002/cbic.201200447 ◽

2012 ◽

Vol 13 (16) ◽

pp. 2425-2432 ◽

Cited By ~ 35

Author(s):

Wolfgang Bermel ◽

Ivano Bertini ◽

Jordan Chill ◽

Isabella C. Felli ◽

Noam Haba ◽

...

Keyword(s):

Amino Acid ◽

Intrinsically Disordered Proteins ◽

Disordered Proteins ◽

Intrinsically Disordered

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

Journal of Biological System ◽

10.1142/s0218339012400086 ◽

2012 ◽

Vol 20 (04) ◽

pp. 471-511 ◽

Cited By ~ 12

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.

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Conformational Entropy of Intrinsically Disordered Proteins from Amino Acid Triads

Scientific Reports ◽

10.1038/srep11740 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 24

Author(s):

Anupaul Baruah ◽

Pooja Rani ◽

Parbati Biswas

Keyword(s):

Amino Acid ◽

Intrinsically Disordered Proteins ◽

Disordered Proteins ◽

Conformational Entropy ◽

Intrinsically Disordered

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NSP 11 of SARS-CoV-2 is an Intrinsically Disordered Protein

10.1101/2020.10.07.330068 ◽

2020 ◽

Cited By ~ 1

Author(s):

Kundlik Gadhave ◽

Prateek Kumar ◽

Ankur Kumar ◽

Taniya Bhardwaj ◽

Neha Garg ◽

...

Keyword(s):

Amino Acid ◽

Intrinsically Disordered Proteins ◽

Conformational Dynamics ◽

Alpha Helix ◽

Intrinsically Disordered Protein ◽

Disordered Proteins ◽

Helical Conformation ◽

Structural Protein ◽

Intrinsically Disordered ◽

Protein Size

AbstractThe intrinsically disordered proteins/regions (IDPs/IDPRs) are known to be responsible for multiple cellular processes and are associated with many chronic diseases. In viruses, the existence of disordered proteome is also proven and are related with its conformational dynamics inside the host. The SARS-CoV-2 virus has a large proteome, in which, structure and functions of many proteins are not known as of yet. Previously, we have investigated the dark proteome of SARS-CoV-2. However, the disorder status of non-structural protein 11 (nsp11) was not possible because of very small in size, just 13 amino acid long, and for most of the IDP predictors, the protein size should be at least 30 amino acid long. Also, the structural dynamics and function status of nsp11 was not known. Hence, we have performed extensive experimentation on nsp11. Our results, based on the Circular dichroism spectroscopy gives characteristic disordered spectrum for IDPs. Further, we investigated the conformational behaviour of nsp11 in the presence of membrane mimetic environment, alpha helix inducer, and natural osmolyte. In the presence of negatively charged and neutral liposomes, nsp11 remains disordered. However, with SDS micelle, it adopted an α-helical conformation, suggesting the helical propensity of nsp11. At the end, we again confirmed the IDP behaviour of nsp11 using molecular dynamics simulations.

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PETISCO is a novel protein complex required for 21U RNA biogenesis and embryonic viability

10.1101/463711 ◽

2018 ◽

Cited By ~ 1

Author(s):

Ricardo J. Cordeiro Rodrigues ◽

António Miguel de Jesus Domingues ◽

Svenja Hellmann ◽

Sabrina Dietz ◽

Bruno F. M. de Albuquerque ◽

...

Keyword(s):

Protein Complex ◽

Intrinsically Disordered Proteins ◽

Rna Binding ◽

Disordered Proteins ◽

Sequence Motif ◽

C Elegans ◽

Conserved Sequence ◽

Intrinsically Disordered ◽

Rna Biogenesis ◽

Novel Protein

AbstractPiwi proteins are important for germ cell development in almost all animals studied thus far. These proteins are guided to specific targets, such as transposable elements, by small guide RNAs, often referred to as piRNAs, or 21U RNAs in C. elegans. In this organism, even though genetic screens have uncovered a number of potential 21U RNA biogenesis factors, little is known about how these factors interact or what they do. Based on the previously identified 21U biogenesis factor PID-1, we here define a novel protein complex, PETISCO, that is required for 21U RNA biogenesis. PETISCO contains both potential 5’-cap and 5’-phosphate RNA binding domains, suggesting involvement in 5’ end processing. We define the interaction architecture of PETISCO and reveal a second function for PETISCO in embryonic development. This essential function of PETISCO is not mediated by PID-1, but by TOST-1. Vice versa, TOST-1 is not involved in 21U RNA biogenesis. Both PID-1 and TOST-1 are small, intrinsically disordered proteins that interact directly with the PETISCO protein ERH-2 (enhancer of rudimentary homolog 2) using a conserved sequence motif. Finally, our data suggest an important role for TOST-1:PETISCO in SL1 homeostasis in the early embryo. Our work describes the first molecular platform for 21U RNA production in C. elegans, and strengthens the view that 21U RNA biogenesis is built upon a much more widely used, snRNA-related pathway.

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