The role of metals in protein structure and function  Page description

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Details of project

  
Identifier
44730
Type NI
Principal investigator Náray-Szabó, Gábor
Title in Hungarian Fémek szerepe a fehérjeszerkezetben és - működésben
Title in English The role of metals in protein structure and function
Panel Natural Sciences large proposals
Department or equivalent Institute of Chemistry (Eötvös Loránd University)
Participants Barabás, Orsolya
Berente, Imre
Czajlik, András
Farkas, Viktor
Fidy, Judit
Harmat, Veronika
Hollósi, Miklós
Horváth, István
Karancsiné Menyhárd, Dóra
Ovádi, Judit
Pálfi, Villo Katalin
Perczel, András
Szigeti, Krisztián
Takács, Enikő
Vértessy G., Beáta
Starting date 2003-01-01
Closing date 2006-12-31
Funding (in million HUF) 69.000
FTE (full time equivalent) 0.00
state closed project





 

Final report

  
Results in Hungarian
Fehérjekrisztallográfia, mágneses magrezonancia-spektroszkópia és molekulamodellezés segítségével vizsgáltuk az összefüggéseket néhány metalloprotein, valamint egy új típusú, rendezetlen fehérje szerkezete és működése között. Hatékony módszert fejlesztettünk ki a reakcióút kvantummechanikai számítására enzimekben. Tisztáztuk a DNS javításában fontos szerepet játszó dUTPáz által katalizált reakció legtöbb részletét. Meggyőző bizonyítékokat szolgáltattunk arra, hogy az enzimatikus foszfáthidrolízis során a dUTPázban nagy energiájú, trigonális bipiramisos elrendeződésű intermedier keletkezik. Kimutattuk, hogy a KAR-2 nevű molekula más, biszindol típusú ligandumoktól eltérő módon kötődik a kalmodulinhoz, ez magyarázza különleges fiziológiai hatását. Elvégeztük a hemoglobin hem-csoportjainak normál koordináták szerinti analízisét, amiből következtetéseket vontunk le a szerkezetre vonatkozóan. A deformációk azt mutatják, hogy a hem csoport szerkezete érzékeny a molekula távoli részében kötődő effektor jelenlétére, ami az allosztérikus szabályozás hatásmechanizmusának a tercier szerkezettel való kapcsolatát támasztja alá. A közelmúltban egy új agy-specifikus fehérjét izoláltunk, melynek átlagos rendezetlensége 46-47%, tehát szerkezet nélkülinek tekinthető. Részletes vizsgálatokat végeztünk e fehérje, illetve különböző fehérjékkel képezett komplexe szerkezetére vonatkozóan.
Results in English
We investigated the relationship between the structure and activity of some metalloproteins and a new unfolded protein. We developed an efficient method for the quantum mechanical calculation of the reaction path in enzymes. Most details of the reaction catalysed by dUTPase, playing an important role in DNA repair, have been clarified. We provided convincing evidence that during enzymatic phosphate hydrolysis a high-energy, trigonal bipyramidal intermediate is formed. We have shown that the molecule KAR-2, in contrast to other bisindole-type ligands, has a different binding mode to calmodulin, which explains its special physiological effect. We performed the normal co-ordinate analysis of the hem groups of haemoglobin and derived conclusions on their structure. The deformations indicate that the structure of the hem group is sensitive to the presence of an effector bound in a distant region of the molecule. This finding supports the relation between the allosteric mechanism of action and the tertiary structure. Recently we isolated a new brain-specific protein, which is 46 to 47 per cent disordered, i.e. it can be considered as unfolded. We made detailed studies on the structure of this protein and its complex with others.
Full text http://real.mtak.hu/1233/
Decision
Yes





 

List of publications

  
Hudáky P.; Perczel A: A self-stabilized model of the chymotrypsin catalytic pocket. The energy profile of the overall catalytic cycle, PROTEINS: Structure, Function, and Bioinformatics 62:749–759, 2006
Tirián L; Hlavanda E; Oláh J; Horváth I; Orosz F; Szabó B; Kovács J; Szabad J; Ovádi J: TPPP/p25, the first member of a new protein family, promotes tubulin assemblies and blocks mitotic spindle formation, Proceedings of the National Academy of Sciences of the USA 100:13976-13981, 2003
Osváth Sz; Herényi L; Závodszky P; Fidy J; Köhler G: Hierarchic finite level energy landscape model of protein folding to describe the refolding of phosphoglycerate kinase, Journal of Biological Chemistry, in press, 2006
Osváth Sz; Jackel M; Agócs G; Závodszky P; Köhler G; Fidy J: Domain interactions direct misfolding and amyloid formation of yeast phosphoglycerate kinase., PROTEINS: Structure, function and bioinformatics, 62:909-917, 2006
Osváth Sz; Köhler G; Závodszky P; Fidy J;: Asymmetric effect of domain interactions on the kinetics of folding in yeast phosphoglycerate kinase., Protein Science 14:1609-1616, 2005
Keller A; Peltzer J; Carpentier G; Horváth I; Oláh J; Duchesnay J; Orosz F; Ovádi J: Interactions of enolase isoforms with microtubules during myogenesis, Biochemical and Biophysical Reseacrh Communications, 2006
Oláh J; Tőkési N; Vincze O; Horváth I; Lehotzky A; Erdei A; Szájli E; Medzihradszky KM; Orosz F; Kovács GG; Ovádi J: Interaction of TPPP/p25 protein with glyceraldehyde-3-phosphate dehydrogenase and their co-localization in Lewy bodies, Journal of Biological Chemistry, in press, 2006
Vincze O; Tőkési N; Hlavanda E; Zotter A, Horváth I; Oláh J, Lehotzky A, Perczel A, Vass E; Tirián L, Medzihradszky KF; Kovács J, Orosz F, Ovádi J: TPPP/p25 homologues, p20 and p18: New proteins with distinct structures and functions, FASEB Journal, under revision, 2006
Orosz F; Horváth I; Ovádi J: New anti-cancer drugs with distinct anti-calmodulin activity, Mini-review in Medicinal Chemistry, 2006
Orosz F; Kovács GG; Lehotzky A; Oláh J; Vincze O; Ovádi J: TPPP/p25: from unfolded protein to misfolding disease: prediction and experiments., Biology of the Cell 96:701-711, 2004
Kovács GG; László L; Kovács J; Jensen PH; Lindersson E; Botond G; Molnár T; Perczel A; Hudecz F; Mező G; Erdei A; Tirián L; Lehotzky A; Gelpi E; Budka H; Ovádi J: Natively unfolded tubulin polymerization promoting protein TPPP/p25 is a common marker of alpha-synucleinopathies, Neurobiology of Disease 17:155-162., 2004
Ovádi J; Orosz F; Hollán Zs: Functional aspects of cellular microcompartmentation in the development of neurodegeneration. Mutation-induced aberrant protein-protein associations, Molecular and Cellular Biochemistry 256:83-93, 2003
Oláh J; Orosz F; Puskás LG; Hackler L; Horányi M; Polgár L; Hollán S; Ovádi J: Triosephosphate isomerase deficiency: Consequences of an inherited mutation at mRNA, protein and metabolic levels, Biochemical Journal 392:675-683, 2005
Lehotzky A; Tirián L; Tőkési N; Lenárt P; Szabó B; Kovács J; Ovádi J: Dynamic targeting of microtubules by TPPP/p25 affects cell survival., Journal of Cell Sciences 117:6249-6259., 2004
Kovári J; Barabás O; Takács E; Békési A; Dubrovay Zs; Pongrácz V; Zagyva I ; Imre T; Szabó P; Vértessy BG: Altered active site flexibility and a structural metal-binding site in eukaryotic dUTPase. Kinetic characterization, folding and crystallographic studies of the homotrimeric Drosophila enzyme., Journal of Biological Chemistry 279:17932-17944, 2004
Barabás O; Németh V; Vértessy BG: Crystallization and preliminary X-ray studies of dUTPase from Mason-Pfizer monkey retrovirus, Acta Crystallographica Sect F 62:399-401, 2006
Mustafi D; Békési A; Vértessy BG; Makinen MW: The catalytic and structural role of the metal ion in dUTP pyrophosphatase, Proceedings of the National Academy of Sciences of the USA 100:5670-5675, 2003
Barabás O; Pongrácz V; Kovári J; Wilmanns M; Vértessy BG: Structural insights into the catalytic mechanism of phosphate ester hydrolysis by dUTPase, Journal of Biological Chemistry 279:42907-42915, 2004
Takács E; Grolmusz VK; Vértessy BG: A tradeoff between protein stability and conformational mobility in homotrimeric dUTPases, FEBS Letters 566:48-54, 2004
Békési A; Zagyva I; Hunyadi-Gulyás E; Pongrácz V; Kovári J; Nagy AO; Erdei A; Medzihradszky KF; Vértessy BG: Developmental regulation of dUTPase in Drosophila melanogaster, Journal of Biological Chemistry 279:22362-22370, 2004
Dubrovay Z; Gáspári Z; Hunyadi-Gulyás E; Medzihradszky KF; Perczel A; Vértessy BG: Multidimensional NMR identifies the conformational shift essential for catalytic competence in the 60-kDa Drosophila melanogaster dUTPase trimer., Journal of Biological Chemistry 279:17945-17950, 2004
Berente I; Náray-Szabó G: Energy decomposition scheme for combined ab initio quantum mechanical/molecular mechanical methods, International Journal of Quantum Chemistry 104:328-334, 2005
Berente I; Czinki E; Náray-Szabó G: A combined electronegativity equalization and electrostatic potential fit method for the determination of atomic point charges, Journal of Computational Chemistry, in press, 2006
Berente I; Náray-Szabó G: Multicoordinate driven method for approximating enzymatic reaction paths: Automatic definition of the reaction coordinate using a subset of chemical coordinates, Journal of Physical Chemistry A 110:772-778, 2006
Kovári J; Imre T; Szabó P; Vértessy BG: Mechanistic studies of dUTPases, Nucleosides Nucleotides Nucleic Acids 23:1475-1479, 2004
Horváth I; Harmat V; Perczel A; Pálfi V; Nyitray L; Nagy A; Hlavanda E; Náray-Szabó G; Ovádi J: The structure of the complex of calmodulin with KAR-2: a novel mode of binding explains the unique pharmacology of the drug, Journal of Biological Chemistry 280:8266-8274, 2005
Barabás O; Rumlova M; Erdei A; Pongrácz V; Pichová I; Vértessy BG: dUTPase and nucleocapsid polypeptides of the Mason-Pfizer monkey virus form a fusion protein in the virion with homotrimeric organization and low catalytic efficiency, Journal of Biological Chemistry 278:38803-38812, 2003
Schay G; Smeller L; Tsuneshige A; Yonetani T; Fidy J: Allosteric effectors influence the tetrameric stability of both R and T states of hemoglobin A, Journal of Biological Chemistry, in press, 2006
Kövesi I; Schay G; Yonetani T; Laberge M; Fidy J: High pressure reveals that the stability of interdimeric contacts in the R- and T- state of HbA is influenced by allosteric effectors:Insights from computational simulations, BBA Proteins and Proteomics, 1764:516-521, 2006
Laberge M; Kövesi I; Yonetani T; Fidy J: Hemoglobin bound to heterotropic effectors: Models of the DPG, IHP and RSR13 binding sites, FEBS Letters 579:627-632, 2005
Laberge M; Yonetani T; Fidy J: Normal coordinate structural decomposition of the heme distortions of hemoglobin in various quaternary states and bound to allosteric effectors, Molecular Diversity 7:15-23, 2003
Szarvas Sz; Szalay L; Vass E; Hollósi M; Samu E; Huszthy P: Chiroptical properties of cation complexes of chiral phenazino-18-crown-6 ether-type hosts, Chirality 17:1-7, 2005
Hudáky P; Perczel A: Conformation dependence of pKa: Ab initio and DFT investigation of histidine, Journal of Physical Chemistry A108:6195-6205, 2004
Lá ng A; Csizmadia IG; Perczel A: Peptide models XLV: Conformational properties of N-formyl-L-methioninamide and its relevance to methionine in proteins, PROTEINS: Structure, Function, and Bioinformatics 58:571–588, 2005
Beke T; Csizmadia IG; Perczel A: Theoretical study on tertiary structural elements of beta-peptides: Nanotubes formed from parallel-sheet-derived assemblies of beta-peptides, Journal of the American Chemical Society 128:5158-5167, 2006
Hudáky P; Perczel A: Toward direct determination of conformations of protein building units from multidimensional NMR experiments VI. Chemical shift analysis of His to gain 3D structure and protonation state information, Journal of Computational Chemistry 26:1307–1317, 2005



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