@misc{10481/71178,
year = {2021},
month = {10},
url = {http://hdl.handle.net/10481/71178},
abstract = {The multifunctional nature of human flavoproteins is critically linked to their ability to populate multiple conformational states. Ligand binding, post-translational modifications and disease-associated mutations can reshape this functional landscape, although the structure-function relationships of these effects are not well understood. Herein, we characterized the structural and functional consequences of two mutations (the cancer associated P187S and the phosphomimetic S82D) on different ligation states which are relevant to flavin binding, intracellular stability and catalysis of the disease-associated NQO1 flavoprotein. We found that these mutations affected the stability locally and their effects propagated differently through the protein structure depending both on the nature of the mutation and the ligand bound, showing directional preference from the mutated site and leading to specific phenotypic manifestations in different functional traits (FAD binding, catalysis and inhibition, intracellular stability and pharmacological response to ligands). Our study thus supports that pleitropic effects of disease-causing mutations and phosphorylation events on human flavoproteins may be caused by longrange structural propagation of stability effects to different functional sites that depend on the ligation-state and site-specific perturbations. Our approach can be of general application to investigate these pleiotropic effects at the flavoproteome scale in the absence of high-resolution structural models.},
organization = {ERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency	RTI2018-096246-B-I00- SAF2015-69796},
organization = {Junta de Andalucia	P11-CTS-7187- P18-RT-2413},
organization = {Aula FUNCANIS-UGR},
organization = {European Commission	731077},
organization = {Spanish Ministry of Science and Innovation-State Research Agency	PID2019-103901 GB-I00},
organization = {Gobierno de Aragon-FEDER	E35_20R},
organization = {BioCeV center	CZ.1.05/1.1.00/02.0109},
organization = {CMS/CIISB facility	MEYS CZ-LM2018127},
organization = {Department of Biotechnology (DBT) India	BT/PR26099/BID/7/811/2017},
organization = {Science, Engineering and Research Board (SERB, India)	MTR/2019/000392},
publisher = {Elsevier},
keywords = {Flavoprotein},
keywords = {Multifunctional proteins},
keywords = {Ligand binding},
keywords = {Disease-causing mutation},
keywords = {Post-translational modification},
keywords = {NQO1},
title = {Structural basis of the pleiotropic and specific phenotypic consequences of  missense mutations in the multifunctional NAD(P)H:quinone  oxidoreductase 1 and their pharmacological rescue},
doi = {10.1016/j.redox.2021.102112},
author = {Pacheco García, Juan Luis and Palomino Morales, Rogelio Jesús and Mesa-Torres, Noel and Pey Rodríguez, Ángel Luis},
}