Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach.
Panagis PolykretisEnrico LuchinatAlessio BonucciAndrea GiachettiMelissa A GraewertDmitri I SvergunLucia BanciPublished in: IUCrJ (2019)
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.
Keyphrases
- oxidative stress
- magnetic resonance
- cell death
- endoplasmic reticulum stress
- protein protein
- cell cycle arrest
- amino acid
- molecular dynamics simulations
- binding protein
- high resolution
- signaling pathway
- computed tomography
- gene expression
- induced apoptosis
- machine learning
- molecular dynamics
- small molecule
- magnetic resonance imaging
- lps induced
- nuclear factor
- single molecule
- copy number
- pi k akt
- dna methylation
- electron microscopy
- energy transfer
- dual energy