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Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach

The X-chromosome-linked inhibitor of apoptosis protein (XIAP) is a multidomain protein whose main function is to block apoptosis by caspase inhibition. XIAP is also involved in other signalling pathways, including NF-κB activation and copper homeostasis. XIAP is overexpressed in tumours, potentiatin...

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Autores principales: Polykretis, Panagis, Luchinat, Enrico, Bonucci, Alessio, Giachetti, Andrea, Graewert, Melissa A., Svergun, Dmitri I., Banci, Lucia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760453/
https://www.ncbi.nlm.nih.gov/pubmed/31576227
http://dx.doi.org/10.1107/S205225251901073X
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author Polykretis, Panagis
Luchinat, Enrico
Bonucci, Alessio
Giachetti, Andrea
Graewert, Melissa A.
Svergun, Dmitri I.
Banci, Lucia
author_facet Polykretis, Panagis
Luchinat, Enrico
Bonucci, Alessio
Giachetti, Andrea
Graewert, Melissa A.
Svergun, Dmitri I.
Banci, Lucia
author_sort Polykretis, Panagis
collection PubMed
description The X-chromosome-linked inhibitor of apoptosis protein (XIAP) is a multidomain protein whose main function is to block apoptosis by caspase inhibition. XIAP is also involved in other signalling pathways, including NF-κB activation and copper homeostasis. XIAP is overexpressed in tumours, potentiating cell survival and resistance to chemotherapeutics, and has therefore become an important target for the treatment of malignancy. Despite the fact that the structure of each single domain is known, the conformation of the full-length protein has never been determined. Here, the first structural model of the full-length XIAP dimer, determined by an integrated approach using nuclear magnetic resonance, small-angle X-ray scattering and electron paramagnetic resonance data, is presented. It is shown that XIAP adopts a compact and relatively rigid conformation, implying that the spatial arrangement of its domains must be taken into account when studying the interactions with its physiological partners and in developing effective inhibitors.
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spelling pubmed-67604532019-10-01 Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach Polykretis, Panagis Luchinat, Enrico Bonucci, Alessio Giachetti, Andrea Graewert, Melissa A. Svergun, Dmitri I. Banci, Lucia IUCrJ Research Papers The X-chromosome-linked inhibitor of apoptosis protein (XIAP) is a multidomain protein whose main function is to block apoptosis by caspase inhibition. XIAP is also involved in other signalling pathways, including NF-κB activation and copper homeostasis. XIAP is overexpressed in tumours, potentiating cell survival and resistance to chemotherapeutics, and has therefore become an important target for the treatment of malignancy. Despite the fact that the structure of each single domain is known, the conformation of the full-length protein has never been determined. Here, the first structural model of the full-length XIAP dimer, determined by an integrated approach using nuclear magnetic resonance, small-angle X-ray scattering and electron paramagnetic resonance data, is presented. It is shown that XIAP adopts a compact and relatively rigid conformation, implying that the spatial arrangement of its domains must be taken into account when studying the interactions with its physiological partners and in developing effective inhibitors. International Union of Crystallography 2019-08-23 /pmc/articles/PMC6760453/ /pubmed/31576227 http://dx.doi.org/10.1107/S205225251901073X Text en © Panagis Polykretis et al. 2019 http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.http://creativecommons.org/licenses/by/4.0/
spellingShingle Research Papers
Polykretis, Panagis
Luchinat, Enrico
Bonucci, Alessio
Giachetti, Andrea
Graewert, Melissa A.
Svergun, Dmitri I.
Banci, Lucia
Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach
title Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach
title_full Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach
title_fullStr Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach
title_full_unstemmed Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach
title_short Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach
title_sort conformational characterization of full-length x-chromosome-linked inhibitor of apoptosis protein (xiap) through an integrated approach
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760453/
https://www.ncbi.nlm.nih.gov/pubmed/31576227
http://dx.doi.org/10.1107/S205225251901073X
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