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      The AAA + ATPase valosin-containing protein (VCP)/p97/Cdc48 interaction network in Leishmania

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          Abstract

          Valosin‐containing protein (VCP)/p97/Cdc48 is an AAA + ATPase associated with many ubiquitin-dependent cellular pathways that are central to protein quality control. VCP binds various cofactors, which determine pathway selectivity and substrate processing. Here, we used co-immunoprecipitation and mass spectrometry studies coupled to in silico analyses to identify the Leishmania infantum VCP ( LiVCP) interactome and to predict molecular interactions between LiVCP and its major cofactors. Our data support a largely conserved VCP protein network in Leishmania including known but also novel interaction partners. Network proteomics analysis confirmed LiVCP-cofactor interactions and provided novel insights into cofactor-specific partners and the diversity of LiVCP complexes, including the well-characterized VCP -UFD1-NPL4 complex. Gene Ontology analysis coupled with digitonin fractionation and immunofluorescence studies support cofactor subcellular compartmentalization with either cytoplasmic or organellar or vacuolar localization. Furthermore, in silico models based on 3D homology modeling and protein–protein docking indicated that the conserved binding modules of LiVCP cofactors, except for NPL4, interact with specific binding sites in the hexameric LiVCP protein, similarly to their eukaryotic orthologs. Altogether, these results allowed us to build the first VCP protein interaction network in parasitic protozoa through the identification of known and novel interacting partners potentially associated with distinct VCP complexes.

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          Clustal Omega for making accurate alignments of many protein sequences.

          Clustal Omega is a widely used package for carrying out multiple sequence alignment. Here, we describe some recent additions to the package and benchmark some alternative ways of making alignments. These benchmarks are based on protein structure comparisons or predictions and include a recently described method based on secondary structure prediction. In general, Clustal Omega is fast enough to make very large alignments and the accuracy of protein alignments is high when compared to alternative packages. The package is freely available as executables or source code from www.clustal.org or can be run on-line from a variety of sites, especially the EBI www.ebi.ac.uk.
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            HDOCK: a web server for protein–protein and protein–DNA/RNA docking based on a hybrid strategy

            Abstract Protein–protein and protein–DNA/RNA interactions play a fundamental role in a variety of biological processes. Determining the complex structures of these interactions is valuable, in which molecular docking has played an important role. To automatically make use of the binding information from the PDB in docking, here we have presented HDOCK, a novel web server of our hybrid docking algorithm of template-based modeling and free docking, in which cases with misleading templates can be rescued by the free docking protocol. The server supports protein–protein and protein–DNA/RNA docking and accepts both sequence and structure inputs for proteins. The docking process is fast and consumes about 10–20 min for a docking run. Tested on the cases with weakly homologous complexes of <30% sequence identity from five docking benchmarks, the HDOCK pipeline tied with template-based modeling on the protein–protein and protein–DNA benchmarks and performed better than template-based modeling on the three protein–RNA benchmarks when the top 10 predictions were considered. The performance of HDOCK became better when more predictions were considered. Combining the results of HDOCK and template-based modeling by ranking first of the template-based model further improved the predictive power of the server. The HDOCK web server is available at http://hdock.phys.hust.edu.cn/.
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              A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol.

              Elimination of misfolded proteins from the endoplasmic reticulum (ER) by retro-translocation is an important physiological adaptation to ER stress. This process requires recognition of a substrate in the ER lumen and its subsequent movement through the membrane by the cytosolic p97 ATPase. Here we identify a p97-interacting membrane protein complex in the mammalian ER that links these two events. The central component of the complex, Derlin-1, is a homologue of Der1, a yeast protein whose inactivation prevents the elimination of misfolded luminal ER proteins. Derlin-1 associates with different substrates as they move through the membrane, and inactivation of Derlin-1 in C. elegans causes ER stress. Derlin-1 interacts with US11, a virally encoded ER protein that specifically targets MHC class I heavy chains for export from the ER, as well as with VIMP, a novel membrane protein that recruits the p97 ATPase and its cofactor.
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                Author and article information

                Contributors
                barbara.papadopoulou@crchudequebec.ulaval.ca
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                4 August 2020
                4 August 2020
                2020
                : 10
                : 13135
                Affiliations
                [1 ]ISNI 0000 0000 9471 1794, GRID grid.411081.d, Division of Infectious Disease and Immunity, , CHU de Quebec Research Center-Laval University, ; 2705 Laurier Blvd, Quebec, QC G1V 4G2 Canada
                [2 ]ISNI 0000 0004 1936 8390, GRID grid.23856.3a, Department of Microbiology-Infectious Disease and Immunology, Faculty of Medicine, , University Laval, ; Quebec, QC G1V 4G2 Canada
                [3 ]ISNI 0000 0001 2176 3398, GRID grid.412380.c, Present Address: Department of Community Medicine, , Federal University of Piauí, ; Teresina, Brazil
                [4 ]ISNI 0000 0004 1936 8390, GRID grid.23856.3a, Institut de Biologie Intégrative Et Des Systèmes (IBIS), , Laval University, ; Quebec, QC Canada
                Article
                70010
                10.1038/s41598-020-70010-4
                7403338
                32753747
                2dc7f9e7-9642-4b03-b6c8-b5717b82afbd
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 November 2019
                : 14 July 2020
                Funding
                Funded by: Canadian Institutes of Health Research
                Award ID: Operating grant MOP-12182
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized
                microbiology,parasite biology,proteomics,protein-protein interaction networks,gene ontology,network topology,protein structure predictions

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