TP-MV: Therapeutic protein prediction by multi-view learning

Background: Therapeutic peptide prediction is critical for drug development and therapy. Researchers have been studying this essential task, developing several computational methods to identify different therapeutic peptide types. Objective: Most predictors are the specific methods for certain peptides. Currently, developing methods to predict the presence of multiple peptides remains a challenging problem. Moreover, it is still challenging to combine different features to make the therapeutic prediction. Method: In this paper, we proposed a new ensemble method TP-MV for general therapeutic peptide recognition. TP-MV is developed using the stacking framework in conjunction with the KNN, SVM, ET, RF, and XGB. Then TP-MV constructs a multi-view learning model as meta-classifiers to extract the discriminative feature for different peptides. Results: In the experiment, the proposed method outperforms the other existing methods on the benchmark datasets, indicating that the proposed method has the ability to predict multiple therapeutic peptides simultaneously. Conclusion: The TP-MV is a useful tool for predicting therapeutic peptides.

Molecular Modeling of Signal Peptide Recognition by Eukaryotic Sec Complexes

Here, we review recent molecular modelling and simulation studies of the Sec translocon, the primary component/channel of protein translocation into the endoplasmic reticulum (ER) and bacterial periplasm, respectively. Our focus is placed on the eukaryotic Sec61, but we also mention modelling studies on prokaryotic SecY since both systems operate in related ways. Cryo-EM structures are now available for different conformational states of the Sec61 complex, ranging from the idle or closed state over an inhibited state with the inhibitor mycolactone bound near the lateral gate, up to a translocating state with bound substrate peptide in the translocation pore. For all these states, computational studies have addressed the conformational dynamics of the translocon with respect to the pore ring, the plug region, and the lateral gate. Also, molecular simulations are addressing mechanistic issues of insertion into the ER membrane vs. translocation into the ER, how signal-peptides are recognised at all in the translocation pore, and how accessory proteins affect the Sec61 conformation in the co- and post-translational pathways.

Discovery of a caspase cleavage motif antibody reveals insights into noncanonical inflammasome function

Inflammasomes sense a number of pathogen and host damage signals to initiate a signaling cascade that triggers inflammatory cell death, termed pyroptosis. The inflammatory caspases (1/4/5/11) are the key effectors of this process through cleavage and activation of the pore-forming protein gasdermin D. Caspase-1 also activates proinflammatory interleukins, IL-1β and IL-18, via proteolysis. However, compared to the well-studied apoptotic caspases, the identity of substrates and therefore biological functions of the inflammatory caspases remain limited. Here, we construct, validate, and apply an antibody toolset for direct detection of neo-C termini generated by inflammatory caspase proteolysis. By combining rabbit immune phage display with a set of degenerate and defined target peptides, we discovered two monoclonal antibodies that bind peptides with a similar degenerate recognition motif as the inflammatory caspases without recognizing the canonical apoptotic caspase recognition motif. Crystal structure analyses revealed the molecular basis of this strong yet paradoxical degenerate mode of peptide recognition. One antibody selectively immunoprecipitated cleaved forms of known and unknown inflammatory caspase substrates, allowing the identification of over 300 putative substrates of the caspase-4 noncanonical inflammasome, including caspase-7. This dataset will provide a path toward developing blood-based biomarkers of inflammasome activation. Overall, our study establishes tools to discover and detect inflammatory caspase substrates and functions, provides a workflow for designing antibody reagents to study cell signaling, and extends the growing evidence of biological cross talk between the apoptotic and inflammatory caspases.

Diversity of the BoLA-DRB3 Gene in Cattle Breeds From Tropical and Subtropical Regions of South America

Background Bovine leukocyte antigens (BoLA) are widely used as markers of disease and immunological traits in cattle because of their primary function in the recognition of pathogens by the immune system. To date, however, the characterization of BoLA gene polymorphisms in Latin American Zebu and mixed zebuine breeds is scarce. By a sequence-based typing method, here we sequenced exon 2 of BoLA class II DRB3 gene of 264 animals from the five breeds (Creole, Brahman, Braford, Brangus and Nellore) most commonly used in northern Argentina. Results The taurine and zebuine breeds contained 61 previously reported alleles. Genetic diversity was high at allelic and molecular levels, particularly in the mixed breeds. Neutrality tests revealed that none of the breeds shows the even gene frequency distribution expected under a balanced selection scenario. The FST index shows significant differences across all populations (FST=0.052, P < 0.001), indicating a substantial differentiation between breeds. UPGMA trees and Metric multidimensional scaling (MDS) analysis show that, as expected, Creole is distantlyrelated to the other zebuinebreeds. Among them, Brahman, Braford and Brangus cluster closer together than with Nellore. These data are consistent with the historical and geographical origin of these breeds. A peptide binding region sequence analysis at the aminoacid level revealed that, despite the nucleotide diversity among the breeds, the key aminoacids involved in peptide recognition are greatly conserved. Conclusions This is the first report of BoLA-DRB3 diversity in pure and mixed zebuine cattle breeds from Argentina. Knowledge ofBoLA-DRB3 variability in breeds adapted to tropical and subtropical environments contributes not only to ongoing efforts to catalog bovine MHC allele frequencies by breed and location but also to the design of peptide-based vaccines.

Mannosylated adamantane-containing desmuramyl peptide recognition by NOD2 receptor: a molecular dynamics study

Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular receptor that recognizes the bacterial peptidoglycan fragment, muramyl dipeptide (MDP). Our group has synthesized and biologically evaluated desmuramyl peptides containing adamantane and...