# XIAP

## Overview
The XIAP gene encodes the X-linked inhibitor of apoptosis protein, a critical regulator of programmed cell death. XIAP is a member of the inhibitor of apoptosis protein (IAP) family and is characterized by its ability to inhibit caspases, the enzymes responsible for executing apoptosis. The protein is composed of multiple domains, including three Baculoviral IAP Repeat (BIR) domains, a ubiquitin-associated (UBA) domain, and a C-terminal Really Interesting New Gene (RING) domain, which confers E3 ubiquitin ligase activity. These structural features enable XIAP to bind and inhibit caspases-3, -7, and -9, thereby preventing apoptosis and contributing to cellular homeostasis (Polykretis2019Conformational; Riedl2001Structural). XIAP is ubiquitously expressed in human tissues and plays a significant role in various cellular processes, including immune response and inflammation. Mutations in the XIAP gene are associated with X-linked lymphoproliferative syndrome type 2 (XLP-2), highlighting its clinical significance in immune regulation and disease (Latour2015XIAP; Damgaard2013Disease‐causing).

## Structure
The X-linked inhibitor of apoptosis protein (XIAP) is a multidomain protein that plays a crucial role in inhibiting apoptosis by blocking caspase activity. XIAP is composed of 497 amino acids and is expressed in most human tissues. It contains three Baculoviral IAP Repeat (BIR) domains, a ubiquitin-associated (UBA) domain, and a C-terminal Really Interesting New Gene (RING) domain, which is involved in E3 ubiquitin ligase activity (Polykretis2019Conformational). The BIR domains are zinc-binding motifs, with the BIR2 domain specifically inhibiting caspases-3 and -7, and the BIR3 domain inhibiting caspase-9 (Riedl2001Structural; Liu2000Structural).

The BIR domains are characterized by a three-stranded antiparallel β-sheet and four α-helices, resembling a classical zinc finger structure (Sun1999NMR). The BIR2 domain, in particular, has a globular structure with an N-terminal extension that interacts with caspase-3, forming a noncovalent, reversible inhibitor (Riedl2001Structural). XIAP's full-length structure is compact and relatively rigid, forming a homodimer in solution, with the dimerization mediated by BIR1-BIR1 and RING-RING interfaces (Polykretis2019Conformational).

XIAP undergoes post-translational modifications such as ubiquitination, which affects its stability and function. The protein's structural features are crucial for its interactions with physiological partners and the development of effective inhibitors (Polykretis2019Conformational).

## Function
XIAP (X-linked inhibitor of apoptosis protein) is a crucial regulator of apoptosis in healthy human cells. It functions primarily by inhibiting caspases, which are proteases responsible for executing apoptosis. XIAP directly binds to and inhibits initiator caspase-9 and effector caspases-3 and -7, preventing the apoptotic process (Jost2019Regulation; Holcik2001XIAP:apoptoticbrakeandpromisingtherapeutictarget). This inhibition is facilitated by the Baculoviral Inhibitor of apoptosis Repeat (BIR) domains within XIAP, which interact with the active sites of these caspases (Suzuki2001Xlinked).

XIAP is predominantly located in the cytoplasm, where it plays a protective role against various apoptotic triggers, such as UV-irradiation and chemotherapy drugs (Holcik2001XIAP:apoptoticbrakeandpromisingtherapeutictarget). Its activity is regulated by proteins like Smac/DIABLO and XAF1, which can neutralize XIAP's caspase-inhibiting function (Holcik2001XIAP:apoptoticbrakeandpromisingtherapeutictarget).

Beyond apoptosis inhibition, XIAP also functions as an E3 ubiquitin ligase, promoting the ubiquitination and degradation of target proteins, including caspases, thus regulating their activity (Holcik2001XIAP:apoptoticbrakeandpromisingtherapeutictarget; Galbán2009XIAP). This dual role in inhibiting caspase activity and promoting protein degradation is essential for maintaining cellular homeostasis and preventing excessive cell death.

## Clinical Significance
Mutations in the XIAP gene, also known as BIRC4, are linked to X-linked lymphoproliferative syndrome type 2 (XLP-2), a rare primary immunodeficiency. This condition is characterized by a heightened susceptibility to Epstein-Barr virus (EBV) infections, hemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD), and splenomegaly (Latour2015XIAP; Damgaard2013Disease‐causing). XIAP deficiency results from various mutations, including nonsense, missense, deletions, and insertions, which often lead to a complete loss of protein expression (Latour2015XIAP). 

The deficiency is associated with immune dysregulation, increased apoptosis of lymphocytes, and impaired NOD2-dependent immune signaling, contributing to the clinical manifestations of XLP-2 (Rigaud2006XIAP; Damgaard2013Disease‐causing). Patients with XIAP mutations may experience recurrent HLH, chronic colitis, and other inflammatory conditions, often with a complicated course and unresponsiveness to standard treatments (Parackova2020Novel; Yang2012Clinical). 

Female carriers of XIAP mutations are generally asymptomatic due to X chromosome inactivation, although some symptomatic cases have been reported (Latour2015XIAP). The only causal therapy currently available for XIAP deficiency is hematopoietic stem cell transplantation, though gene therapy is being explored (Parackova2020Novel).

## Interactions
XIAP (X-linked inhibitor of apoptosis protein) is involved in several critical protein-protein interactions that regulate apoptosis and other cellular processes. XIAP inhibits apoptosis by binding to and inhibiting caspases, specifically caspase-3, -7, and -9. The BIR2 domain of XIAP interacts with caspase-3 and caspase-7, while the BIR3 domain is responsible for inhibiting caspase-9 (Eckelman2006Human; Sun1999NMR).

XIAP also interacts with SMAC/DIABLO, a mitochondrial protein that promotes caspase activation. SMAC/DIABLO can bind to XIAP and neutralize its inhibitory effect on caspases, which is crucial for the regulation of apoptosis (Obiol‐Pardo2008Protein–protein). The interaction between XIAP and SMAC/DIABLO occurs at the BIR2 domain, which is also the site for binding with RIP2, a kinase involved in NOD signaling pathways. This interaction is significant for the activation of NF-κB signaling (Lethier2023Structure; Krieg2009XIAP).

XIAP's BIR2 domain also binds to the RIPK2 kinase dimer, which is essential for the scaffold function of RIPK2 in cellular signaling. This interaction does not require RIPK2 phosphorylation, highlighting XIAP's role in NOD signaling pathways (Lethier2023Structure). These interactions underscore XIAP's multifunctional role in apoptosis inhibition and cellular signaling.


## References


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[16. (Parackova2020Novel) Zuzana Parackova, Tomas Milota, Petra Vrabcova, Jitka Smetanova, Michael Svaton, Tomas Freiberger, Veronika Kanderova, and Anna Sediva. Novel xiap mutation causing enhanced spontaneous apoptosis and disturbed nod2 signalling in a patient with atypical adult-onset crohn’s disease. Cell Death &amp; Disease, June 2020. URL: http://dx.doi.org/10.1038/s41419-020-2652-4, doi:10.1038/s41419-020-2652-4. This article has 16 citations.](https://doi.org/10.1038/s41419-020-2652-4)

[17. (Lethier2023Structure) Mathilde Lethier, Karine Huard, Michael Hons, Adrien Favier, Bernhard Brutscher, Elisabetta Boeri Erba, Derek W Abbott, Stephen Cusack, and Erika Pellegrini. Structure shows that the bir2 domain of e3 ligase xiap binds across the ripk2 kinase dimer interface. Life Science Alliance, 6(11):e202201784, September 2023. URL: http://dx.doi.org/10.26508/lsa.202201784, doi:10.26508/lsa.202201784. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.26508/lsa.202201784)