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001-es BibID:	BIBFORM049596
Első szerző:	Lábas Anikó
Cím:	Optimization of reorganization energy drives evolution of the designed Kemp eliminase KE07 / A. Labas, E. Szabo, L. Mones, M. Fuxreiter
Dátum:	2013
ISSN:	1570-9639
Megjegyzések:	Understanding enzymatic evolution is essential to engineer enzymes with improved activities or to generate enzymes with tailor-made activities. The computationally designed Kemp eliminase KE07 carries out an unnatural reaction by converting of 5-nitrobenzisoxazole to cyanophenol, but its catalytic efficiency is significantly lower than those of natural enzymes. Three series of designed Kemp eliminases (KE07, KE70, KE59) were shown to be evolvable with considerable improvement in catalytic efficiency. Here we use the KE07 enzyme as a model system to reveal those forces, which govern enzymatic evolution and elucidate the key factors for improving activity. We applied the Empirical Valence Bond (EVB) method to construct the free energy pathway of the reaction in the original KE07 design and the evolved R7 1/3H variant. We analyzed catalytic effect of residues and demonstrated that not all mutations in evolution are favorable for activity. In contrast to the small decrease in the activation barrier, in vitro evolution significantly reduced the reorganization energy. We developed an algorithm to evaluate group contributions to the reorganization energy and used this approach to screen for KE07 variants with potential for improvement. We aimed to identify those mutations that facilitate enzymatic evolution, but might not directly increase catalytic efficiency. Computational results in accord with experimental data show that all mutations, which appear during in vitro evolution were either neutral or favorable for the reorganization energy. These results underscore that distant mutations can also play role in optimizing efficiency via their contribution to the reorganization energy. Exploiting this principle could be a promising strategy for computer-aided enzyme design. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Biochimica et Biophysica Acta (BBA). Proteins and Proteomics. - 1834 : 5 (2013), p. 908-917. -
További szerzők:	Szabó E. Mones, Letif Fuxreiter Mónika (1969-) (kutató vegyész)
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM082447
Első szerző:	Tüű-Szabó Boldizsár
Cím:	Altered dynamics may drift pathological fibrillization in membraneless organelles / B. Tüű-Szabó, G. Hoffka, N. Duro, M. Fuxreiter
Dátum:	2019
ISSN:	1570-9639
Megjegyzések:	Protein phase transition can generate non-membrane bound cellular compartments, which can convert from liquid-like to solid-like states. While the molecular driving forces of phase separation have been largely understood, much less is known about the mechanisms of material-state conversion. We apply a recently developed algorithm to describe the weak interaction network of multivalent motifs, and simulate the effect of pathological mutations. We demonstrate that linker dynamics is critical to the material-state of biomolecular condensates. We show that linker flexibility/mobility is a major regulator of the weak, heterogeneous meshwork of multivalent motifs, which promotes phase transition and maintains a liquid-like state. Decreasing linker dynamics increases the propensity of amyloid-like fragments via hampering the motif-exchange and reorganization of the weak interaction network. In contrast, increasing linker mobility may compensate rigidifying mutations, suggesting that the meshwork of weak, variable interactions may provide a rescue mechanism from aggregation. Motif affinity, on the other hand, has a moderate impact on fibrillization. Here we demonstrate that the fuzzy framework provides an efficient approach to handle the intricate organization of membraneless organelles, and could also be applicable to screen for pathological effects of mutations.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk Matematikai és természettudományok - Kémiai tudományok
Megjelenés:	Biochimica et Biophysica Acta (BBA). Proteins and Proteomics. - 1867 : 10 (2019), p. 988-998. -
További szerzők:	Hoffka Gyula (1992-) (vegyész) Duró Norbert (1990-) (biotechnológus) Fuxreiter Mónika (1969-) (kutató vegyész)
Pályázati támogatás:	GINOP-2.3.2-15-2016-00044 GINOP MTA-DE Lendület MTA Fehérjedinamikai Kutatócsoport
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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