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1

Comparative studies on variability, phylogenesis, and correlated mutations of neuraminidases from influenza virus type A

Filip R., Leluk J.

Bio-Algorithms and Med-Systems

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2018

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Vol. 14, no. 1

art. no. 20170030

EN

Neuraminidase (NA) is an important protein for the replication cycle of influenza A viruses. NA is an enzyme that cleaves the sialic acid receptors; this process plays a significant role in viral life cycle. Blocking NA with a specific inhibitor is an effective way to treat the flu. However, some strains show resistance to current drugs. Therefore, NA is the focus for the intense research for new antiviral drugs and also for the explanation of the functions of new mutations. This research focuses on determining the profile of variability and phylogenetic analysis and finding the correlated mutations within a set of 149 sequences of NA belonging to various strains of influenza A virus. In this study, we have used the original programs (Corm, Consensus Constructor, and SSSSg) and also other bioinformatics software. NA proteins are characterized by various levels of variability in different regions, which was presented in detail with the aid of ConSurf. The use of four independent methods to create the phylogenetic trees gave some new data on the evolutionary relationship within the NA family proteins. The search for correlated mutations shows several potentially important correlated positions that were not reported previously to be significant. The use of such an approach can be potentially important and gives new information regarding NA proteins of influenza A virus.

2

Correlated mutations in hydroxysteroid dehydrogenases family

Żyźniewska A., Leluk J., Żaroffe G.

Bio-Algorithms and Med-Systems

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2017

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Vol. 13, no. 1

17--23

EN

Background: Hydroxysteroid dehydrogenase enzymes belong to the short-chain dehydrogenase/reductase (SDR) superfamily and aldo-keto reductases (AKRs). SDR is involved in the metabolism of many compounds (hormones, lipids, etc.) and is present in almost all studied genomes. Two hundred members of hydroxysteroid dehydrogenases have been analysed in terms of natural mutational variability. The second superfamily comprises AKR superfamily group enzymes whose function is catalysing the oxidation and reduction of many substrates by binding NAD(P)H as a cofactor. This kind of study is the first approach for the hydroxysteroid dehydrogenase family. This information grants practical meaning to designing potential specific drugs to fight specific diseases caused by mutations. Methods: In the research, amino acid sequences of representatives of the hydroxysteroid dehydrogenase family were extracted from the UniProt database. In total, the analysed 200 sequences with the highest degree of similarity were shown by BLAST searches. In the sequence analyses, we used the following software: ClustalX (multiple sequence alignment), Consensus Constructor (creating consensus sequence), and CORM (finding correlated mutations). Results: The CORM program identified potential sites of correlated mutations in hydroxysteroid dehydrogenases. This program generated 18 tables of results that contain the amino acid positions of mutations. Seven of these are presented in this paper. Conclusions: The primary structure of the hydroxysteroid dehydrogenase family shows high variation.

3

Keram: a novel stand-alone application for correlated mutations identification and analysis

Kuśka J., Leluk J., Lesyng B.

Bio-Algorithms and Med-Systems

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2011

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Vol. 7, no. 1

71--76

EN

Keram is a stand-alone Windows 2000/XP/Vista application designed for the detection and analysis of the correlated mutations. Study of this phenomenon provides important information about protein structure stability factors as well as the formation of protein complexes. It is generally assumed that the mechanism of compensation explains the mutations that occur simultaneously. Keram is designed to detect the mutational correlations by comparative analysis of multiple sequence alignments. Additionally a three dimensional structure can be applied to calculate the distance between correlated positions in the protein molecule. Keram has been succesfully applied for the analysis of kinase subfamilies. The obtained data suggest that the mechanism of compensation does not explain utterly this phenomenon which seems to be much more complex and diverse. The residues that are detected as correlated are often placed at very distant positions of the protein structure, therefore the direct mutual interaction between them is impossible. We have detected not only correlated pairs, but also clusters of positions (even more than 10) that reveal correlated changeability.

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Zmienność mutacyjna w homologicznych rodzinach kinaz

Kuśka J., Leluk J., Lesyng B.

Bio-Algorithms and Med-Systems

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2005

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Vol. 1, no. 1/2

125--128

PL

Przeanalizowano cztery rodziny kinaz (heksokinazy, receptorowe kinazy tyrozynowe, niereceptorowe kinazy tyrozynowe- JAK, cAMP-zależne kinazy). Sekwencje pobrano z bazy danych SWISS-PROT. Przeprowadzono dopasowanie sekwencji oraz skonstruowano sekwencje konsensusowe dla każdej rodziny przy użyciu algorytmu semihomologii genetycznej. Do identyfikacji pozycji kontaktujących się wzajemnie w strukturze trzeciorzędowej zastosowano zasoby bazy danych Ligand-Protein Contact and Contacts of Structural. Analiza oraz wizualizacja zmienności dla trzech grup zastała przeprowadzona na podstawie wzorcowej struktury trzeciorzędowej dla każdej grupy, pobranej z Protein Data Bank. Strukturę trzeciorzędową dla grupy JAK wygenerowano w Interdyscyplinarnym Centrum Modelowania Matematycznego i Komputerowego Uniwersytetu Warszawskiego. Przeanalizowano występowanie mutacji sprzężonych w każdej badanej rodzinie enzymów przy użyciu programu Corm, opracowanego również w Interdyscyplinarnym Centrum Modelowania w Warszawie. Dla każdej przebadanej rodziny stwierdzono, że: - W poszczególnych pozycjach występowało od 1 do 17 różnych aminokwasów. – Pozycje tworzące centrum katalityczne wykazują niski stopień zmienności, chociaż pozycje bezpośrednio sąsiadujące z nimi mogą odznaczać się wyższą zmiennością. – N-końcowy peptyd liderowy charakteryzuje się bardzo wysokim stopniem zmienności. – Pozycje znajdujące się w bezpośrednim kontakcie posiadają identyczny lub zbliżony stopień zmienności. – Pozycje wykazujące sprzężenie mutacyjne są odległe od siebie w strukturze pierwszorzędowej, lecz położone blisko siebie w strukturze trzeciorzędowej. To zjawisko potwierdza przyjęty ogólnie mechanizm kompensacji mutacji. Jednak część zaobserwowanych mutacji sprzężonych odnosi się do pozycji znacznie oddalonych od siebie w strukturze trzeciorzędowej. Mechanizm powstawania tego typu sprzężeń mutacyjnych nie jest jeszcze poznany i wymaga dalszych badań. Wyniki naszych badań generalnie potwierdzają hipotezę dotyczącą korelacji pomiędzy poziomem zmienności pozycji będących w kontakcie. Odnosi się to do twierdzenia, że struktura przestrzenna, jak i funkcja białek są bardziej konserwatywne niż struktura pierwszorzędowa. Praca wykonana została w ramach grantu MAMBA (Centre of Excellence for Multiscale Biomolecular Modelling, Bioinformatics and Applications) Projekt nr QLRI-CT-2002-90383.

EN

Four homologous kinase families (hexokinases, RTKs, JAKs, cAMP dependent kinases) were investigated with respect to the mutational variability within each family. The sequences were obtained from Swiss-Prot database. Multiple sequence alignments as well as consensus sequences were created and verified with the aid of the algorithm of genetic semihomology. The application of the Ligand-Protein Contact and Contacts of Structural Units database helped to select the residues which are in mutual contact in the secondary as well as tertiary structures. The analysis and visualization of variability in three analyzed groups was acquired with the use of three-dimensional models obtained from the Protein Data Bank. The tertiary structure of JAKs was predicted at Interdisciplinary Centre for Mathematical and Computational Modelling, Warsaw University. Correlated mutations occurring in each kinase family were identified and investigated with the Corm program developed also at ICM UW. For all four analyzed groups of kinases it was observed that: The results of this work generally confirm the hypothesis concerning the correlation mechanism for mutually interacting residues being in close distance. It refers to the statement that protein structure and function which are more significantly conservative than the primary structure itself. This work was supported by MAMBA (Centre of Excellence for Multiscale Biomolecular Modelling, Bioinformatics and Applications) Project No. QLRI-CT-2002-90383.