scholarly journals In silico model for predicting IL-2 inducing peptides in human

2021 ◽  
Author(s):  
Anjali Lathwal ◽  
Rajesh Kumar ◽  
Dilraj Kaur ◽  
Gajendra P.S. Raghava

Interleukin-2 (IL-2) based immunotherapy has been already approved to treat certain type of cancers as it plays vital role in immune system. Thus it is important to discover new peptides or epitopes that can induce IL-2 with high efficiency. We analyzed experimentally validated IL-2 inducing and non-inducing peptides and observed differ in average amino acid composition, motifs, length, and positional preference of amino acid residues at the N- and C-terminus. In this study, 2528 IL-2 inducing and 2104 non-IL-2 inducing peptides have been used for traning, testing, traing and validation of our models. A large number of machine learning techniques and around 10,000 peptide features have been used for developing prediction models. The Random Forest-based model using hybrid features achieved a maximum accuracy of 73.25%, with AUC of 0.73 on the training set; accuracy of 72.89% with AUC of 0.72 on validation dataset. A web-server IL2pred has been developed for predicting IL-2 inducing peptides, scanning IL-inducing regions in a protein and designing IL-2 specific epitopes by ranking peptide analogs ( https://webs.iiitd.edu.in/raghava/il2pred/ ).

Author(s):  
Anjali Dhall ◽  
Sumeet Patiyal ◽  
Neelam Sharma ◽  
Salman Sadullah Usmani ◽  
Gajendra P S Raghava

Abstract Interleukin 6 (IL-6) is a pro-inflammatory cytokine that stimulates acute phase responses, hematopoiesis and specific immune reactions. Recently, it was found that the IL-6 plays a vital role in the progression of COVID-19, which is responsible for the high mortality rate. In order to facilitate the scientific community to fight against COVID-19, we have developed a method for predicting IL-6 inducing peptides/epitopes. The models were trained and tested on experimentally validated 365 IL-6 inducing and 2991 non-inducing peptides extracted from the immune epitope database. Initially, 9149 features of each peptide were computed using Pfeature, which were reduced to 186 features using the SVC-L1 technique. These features were ranked based on their classification ability, and the top 10 features were used for developing prediction models. A wide range of machine learning techniques has been deployed to develop models. Random Forest-based model achieves a maximum AUROC of 0.84 and 0.83 on training and independent validation dataset, respectively. We have also identified IL-6 inducing peptides in different proteins of SARS-CoV-2, using our best models to design vaccine against COVID-19. A web server named as IL-6Pred and a standalone package has been developed for predicting, designing and screening of IL-6 inducing peptides (https://webs.iiitd.edu.in/raghava/il6pred/).


1988 ◽  
Vol 251 (3) ◽  
pp. 691-699 ◽  
Author(s):  
R W Olafson ◽  
W D McCubbin ◽  
C M Kay

Biochemical and physiological studies of Synechococcus cyanobacteria have indicated the presence of a low-Mr heavy-metal-binding protein with marked similarity to eukaryotic metallothioneins (MTs). We report here the characterization of a Synechococcus prokaryotic MT isolated by gel-permeation and reverse-phase chromatography. The large number of variants of this molecule found during chromatographic separation could not be attributed to the presence of major isoproteins as assessed by amino acid analysis and amino acid sequencing of isoforms. Two of the latter were shown to have identical primary structures that differed substantially from the well-described eukaryotic MTs. In addition to six long-chain aliphatic residues, two aromatic residues were found adjacent to one another near the centre of the molecule, making this the most hydrophobic MT to be described. Other unusual features included a pair of histidine residues located in repeating Gly-His-Thr-Gly sequences near the C-terminus and a complete lack of association of hydroxylated residues with cysteine residues, as is commonly found in eukaryotes. Similarly, aside from a single lysine residue, no basic amino acid residues were found adjacent to cysteine residues in the sequence. Most importantly, sequence alignment analyses with mammalian, invertebrate and fungal MT sequences showed no statistically significant homology aside from the presence of Cys-Xaa-Cys structures common to all MTs. On the other hand, like other MTs, the prokaryotic molecule appears to be free of alpha-helical structure but has a considerable amount of beta-structure, as predicted by both c.d. measurements and the Chou & Fasman empirical relations. Considered together, these data suggested that some similarity between the metal-thiolate clusters of the prokaryote and eukaryote MTs may exist.


Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 715
Author(s):  
Tamara Tomanić ◽  
Claire Martin ◽  
Holly Stefen ◽  
Esmeralda Parić ◽  
Peter Gunning ◽  
...  

Tropomyosins (Tpms) have been described as master regulators of actin, with Tpm3 products shown to be involved in early developmental processes, and the Tpm3 isoform Tpm3.1 controlling changes in the size of neuronal growth cones and neurite growth. Here, we used primary mouse hippocampal neurons of C57/Bl6 wild type and Bl6Tpm3flox transgenic mice to carry out morphometric analyses in response to the absence of Tpm3 products, as well as to investigate the effect of C-terminal truncation on the ability of Tpm3.1 to modulate neuronal morphogenesis. We found that the knock-out of Tpm3 leads to decreased neurite length and complexity, and that the deletion of two amino acid residues at the C-terminus of Tpm3.1 leads to more detrimental changes in neurite morphology than the deletion of six amino acid residues. We also found that Tpm3.1 that lacks the 6 C-terminal amino acid residues does not associate with stress fibres, does not segregate to the tips of neurites, and does not impact the amount of the filamentous actin pool at the axonal growth cones, as opposed to Tpm3.1, which lacks the two C-terminal amino acid residues. Our study provides further insight into the role of both Tpm3 products and the C-terminus of Tpm3.1, and it forms the basis for future studies that aim to identify the molecular mechanisms underlying Tpm3.1 targeting to different subcellular compartments.


2021 ◽  
Author(s):  
Anjali Dhall ◽  
Sumeet Patiyal ◽  
Neelam Sharma ◽  
Naorem Leimarembi Devi ◽  
Gajendra P. S. Raghava

Abstract It has been shown in the past that levels of cytokines, including interleukin 6 (IL6), is highly correlated with the disease severity of COVID-19 patients. IL6 mediated activation of STAT3 is responsible to proliferate proinflammatory responses that leads to promotion of cytokine storm. Thus, STAT3 inhibitors may play a crucial role in managing pathogenesis of COVID-19. This paper describes a method developed for predicting inhibitors against the IL6-mediated STAT3 signaling pathway. The dataset used for training, testing, and evaluation of models contains small-molecule based 1564 STAT3 inhibitors and 1671 non-inhibitors. Analysis of data indicates that rings and aromatic groups are significantly abundant in STAT3 inhibitors compared to non-inhibitors. In order to build models, we generate a wide range of descriptors for each chemical compound. Firstly, we developed models using 2-D and 3-D descriptors and achieved maximum AUC 0.84 and 0.73, respectively. Secondly, fingerprints (FP) are used to build prediction models and achieved 0.86 AUC and accuracy of 78.70% on validation dataset. Finally, models were developed using hybrid features or descriptors, achieve a maximum of 0.87 AUC on the validation dataset. We used our best model to identify STAT3 inhibitors in FDA-approved drugs and found few drugs (e.g., Tamoxifen, and Perindopril) that can be used to manage COVID-19 associated cytokine storm. A webserver “STAT3In” (https://webs.iiitd.edu.in/raghava/stat3in/ ) has been developed to predict and design STAT3 inhibitors.


1989 ◽  
Vol 9 (1) ◽  
pp. 83-91
Author(s):  
S Miyazawa ◽  
T Osumi ◽  
T Hashimoto ◽  
K Ohno ◽  
S Miura ◽  
...  

To identify the topogenic signal of peroxisomal acyl-coenzyme A oxidase (AOX) of rat liver, we carried out in vitro import experiments with mutant polypeptides of the enzyme. Full-length AOX and polypeptides that were truncated at the N-terminal region were efficiently imported into peroxisomes, as determined by resistance to externally added proteinase K. Polypeptides carrying internal deletions in the C-terminal region exhibited much lower import activities. Polypeptides that were truncated or mutated at the extreme C terminus were totally import negative. When the five amino acid residues at the extreme C terminus were attached to some of the import-negative polypeptides, the import activities were rescued. Moreover, the C-terminal 199 and 70 amino acid residues of AOX directed fusion proteins with two bacterial enzymes to peroxisomes. These results are interpreted to mean that the peroxisome targeting signal of AOX residues at the C terminus and the five or fewer residues at the extreme terminus have an obligatory function in targeting. The C-terminal internal region also has an important role for efficient import, possibly through a conformational effect.


2010 ◽  
Vol 432 (3) ◽  
pp. 557-566 ◽  
Author(s):  
Emily R. Slepkov ◽  
Alan Pavinski Bitar ◽  
Hélène Marquis

The intracellular bacterial pathogen Listeria monocytogenes secretes a broad-range phospholipase C enzyme called PC-PLC (phosphatidylcholine phospholipase C) whose compartmentalization and enzymatic activity is regulated by a 24-amino-acid propeptide (Cys28–Ser51). During intracytosolic multiplication, bacteria accumulate the proform of PC-PLC at their membrane–cell-wall interface, whereas during cell-to-cell spread vacuolar acidification leads to maturation and rapid translocation of PC-PLC across the cell wall in a manner that is dependent on Mpl, the metalloprotease of Listeria. In the present study, we generated a series of propeptide mutants to determine the minimal requirement to prevent PC-PLC enzymatic activity and to identify residues regulating compartmentalization and maturation. We found that a single residue at position P1 (Ser51) of the cleavage site is sufficient to prevent enzymatic activity, which is consistent with P1′ (Trp52) being located within the active-site pocket. We observed that mutants with deletions at the N-terminus, but not the C-terminus, of the propeptide are translocated across the cell wall more effectively than wild-type PC-PLC at a physiological pH, and that individual amino acid residues within the N-terminus influence Mpl-mediated maturation of PC-PLC at acidic pH. However, deletion of more than 75% of the propeptide was required to completely prevent Mpl-mediated maturation of PC-PLC. These results indicate that the N-terminus of the propeptide regulates PC-PLC compartmentalization and that specific residues within the N-terminus influence the ability of Mpl to mediate PC-PLC maturation, although a six-residue propeptide is sufficient for Mpl to mediate PC-PLC maturation.


2003 ◽  
Vol 12 (6) ◽  
pp. 1169-1176 ◽  
Author(s):  
Dmitri N. Ermolenko ◽  
John M. Richardson ◽  
George I. Makhatadze

2005 ◽  
Vol 17 (9) ◽  
pp. 1084-1097 ◽  
Author(s):  
W LIM ◽  
Y ZHU ◽  
C WANG ◽  
B TAN ◽  
J ARMSTRONG ◽  
...  

2003 ◽  
Vol 14 (12) ◽  
pp. 4835-4845 ◽  
Author(s):  
Sigrid A. Rajasekaran ◽  
Gopalakrishnapillai Anilkumar ◽  
Eri Oshima ◽  
James U. Bowie ◽  
He Liu ◽  
...  

Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed at high levels in prostate cancer and in tumor-associated neovasculature. In this study, we report that PSMA is internalized via a clathrin-dependent endocytic mechanism and that internalization of PSMA is mediated by the five N-terminal amino acids (MWNLL) present in its cytoplasmic tail. Deletion of the cytoplasmic tail abolished PSMA internalization. Mutagenesis of N-terminal amino acid residues at position 2, 3, or 4 to alanine did not affect internalization of PSMA, whereas mutation of amino acid residues 1 or 5 to alanine strongly inhibited internalization. Using a chimeric protein composed of Tac antigen, the α-chain of interleukin 2-receptor, fused to the first five amino acids of PSMA (Tac-MWNLL), we found that this sequence is sufficient for PSMA internalization. In addition, inclusion of additional alanines into the MWNLL sequence either in the Tac chimera or the full-length PSMA strongly inhibited internalization. From these results, we suggest that a novel MXXXL motif in the cytoplasmic tail mediates PSMA internalization. We also show that dominant negative μ2 of the adaptor protein (AP)-2 complex strongly inhibits the internalization of PSMA, indicating that AP-2 is involved in the internalization of PSMA mediated by the MXXXL motif.


1999 ◽  
Vol 181 (12) ◽  
pp. 3688-3694 ◽  
Author(s):  
Ralf Koebnik

ABSTRACT The N-terminal domain of the OmpA protein from Escherichia coli, consisting of 170 amino acid residues, is embedded in the outer membrane, in the form of an antiparallel β-barrel whose eight transmembrane β-strands are connected by three short periplasmic turns and four relatively large surface-exposed hydrophilic loops. This protein domain serves as a paradigm for the study of membrane assembly of integral β-structured membrane proteins. In order to dissect the structural and functional roles of the surface-exposed loops, they were shortened separately and in all possible combinations. All 16 loop deletion mutants assembled into the outer membrane with high efficiency and adopted the wild-type membrane topology. This systematic approach proves the absence of topogenic signals (e.g., in the form of loop sizes or charge distributions) in these loops. The shortening of surface-exposed loops did not reduce the thermal stability of the protein. However, none of the mutant proteins, with the exception of the variant with the fourth loop shortened, served as a receptor for the OmpA-specific bacteriophage K3. Furthermore, all loops were necessary for the OmpA protein to function in the stabilization of mating aggregates during F conjugation. An OmpA deletion variant with all four loops shortened, consisting of only 135 amino acid residues, constitutes the smallest β-structured integral membrane protein known to date. These results represent a further step toward the development of artificial outer membrane proteins.


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