Abstract
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.
Highlights
The X-chromosome-linked inhibitor of apoptosis protein (XIAP) is a 497-residue cytoplasmic zinc-binding protein that is expressed in most human tissues (Liston et al, 1996; The Human Protein Atlas; https://www.proteinatlas.org/)
XIAP is overexpressed in tumours, potentiating cell survival and resistance to chemotherapeutics, and has become an important target for the treatment of malignancy
XIAP is overexpressed in tumours, where it potentiates cell survival and resistance to chemotherapeutics owing to its antiapoptotic activity
Summary
The X-chromosome-linked inhibitor of apoptosis protein (XIAP) is a 497-residue cytoplasmic zinc-binding protein that is expressed in most human tissues (Liston et al, 1996; The Human Protein Atlas; https://www.proteinatlas.org/). The multifunctional roles of XIAP have raised several questions about how this protein is able to perform so many functions and which are the structural features that allow XIAP to engage in so many interactions All of these processes imply that XIAP constantly interacts with one or more different partners in the cell, and the spatial arrangement of its domains could differently modulate the various interactions. The structures of all of the single domains of XIAP have been characterized (Sun et al, 1999; Liu et al, 2000; Lu et al, 2007; Tse et al, 2011; Lukacs et al, 2013; Nakatani et al, 2013). The obtained models provide the first insight into the spatial arrangement adopted by full-length XIAP in solution
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