X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3) and baculoviral IAP repeat-containing protein 4 (BIRC4), is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that stops
apoptotic
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...
cell death. In humans, this protein (XIAP) is produced by a gene named ''XIAP''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
located on the X
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
.
XIAP is a member of the
inhibitor of apoptosis
Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibit ...
family of proteins (IAP). IAPs were initially identified in
baculovirus
''Baculoviridae'' is a family of viruses. Arthropods, among the most studied being Lepidoptera, Hymenoptera and Diptera, serve as natural hosts. Currently, 85 species are placed in this family, assigned to four genera.
Baculoviruses are known ...
es, but XIAP is one of the homologous proteins found in mammals.
It is so called because it was first discovered by a 273 base pair site on the X chromosome.
The protein is also called human IAP-like Protein (hILP), because it is not as well conserved as the human IAPS:
hIAP-1 and
hIAP-2.
XIAP is the most potent human IAP protein currently identified.
Discovery
Neuronal apoptosis
inhibitor protein (
NAIP) was the first homolog to baculoviral IAPs that was identified in humans.
With the sequencing data of NIAP, the gene sequence for a
RING zinc-finger domain was discovered at site Xq24-25.
Using
PCR and
cloning
Cloning is the process of producing individual organisms with identical or virtually identical DNA, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction. In the field of biotechnology, c ...
, three
BIR domain
The inhibitor of apoptosis domain -- also known as IAP repeat, Baculovirus Inhibitor of apoptosis protein Repeat, or BIR -- is a structural motif found in proteins with roles in apoptosis, cytokine production, and chromosome segregation. Proteins c ...
s and a RING finger were found on the protein, which became known as X-linked Inhibitor of Apoptosis Protein. The transcript size of ''Xiap'' is 9.0kb, with an open reading frame of 1.8kb.
''Xiap'' mRNA has been observed in all human adult and fetal tissues "except peripheral blood leukocytes".
The XIAP sequences led to the discovery of other members of the IAP family.
Structure
XIAP consists of three major types of structural elements (domains). Firstly, there is the
baculoviral IAP repeat (BIR) domain consisting of approximately 70 amino acids, which characterizes all
IAP.
Secondly, there is a UBA domain, which allows XIAP to bind to
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
. Thirdly, there is a zinc-binding domain, or a "carboxy-terminal RING Finger".
XIAP has been characterized with three amino-terminal BIR domains followed by one UBA domain and finally one RING domain.
Between the BIR-1 and BIR-2 domains, there is a linker-BIR-2 region that is thought to contain the only element that comes into contact with the caspase molecule to form the XIAP/Caspase-7 complex.
In solution the full length form of XIAP forms a homodimer of approximately 114 kDa.
Function
XIAP stops
apoptotic
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...
cell death that is induced either by viral infection or by overproduction of
caspases.
Caspases are the enzymes primarily responsible for cell death.
XIAP binds to and inhibits
caspase 3
Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are als ...
,
7 and
9.
The BIR2 domain of XIAP inhibits caspase 3 and 7, while BIR3 binds to and inhibits
caspase 9
Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such ...
.
The RING domain utilizes E3
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
ligase activity and enables IAPs to catalyze ubiquination of self, caspase-3, or caspase-7 by degradation via
proteasome activity.
However,
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s affecting the RING Finger do not significantly affect
apoptosis, indicating that the BIR domain is sufficient for the protein's function.
When inhibiting caspase-3 and caspase-7 activity, the BIR2 domain of XIAP binds to the active-site substrate groove, blocking access of the normal protein substrate that would result in apoptosis.
Caspases are activated by
cytochrome c, which is released into the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
by dysfunctioning
mitochondria.
Studies show that XIAP does not directly affect cytochrome c.
XIAP distinguishes itself from the other human IAPs because it is able to effectively prevent cell death due to "
TNF-α
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
, Fas, UV light, and genotoxic agents".
Inhibiting XIAP
XIAP is inhibited by
DIABLO (Smac) and
HTRA2 (Omi), two death-signaling proteins released into the cytoplasm by the mitochondria.
Smac/DIABLO, a mitochondrial protein and negative regulator of XIAP, can enhance apoptosis by binding to XIAP and preventing it from binding to caspases. This allows normal caspase activity to proceed. The binding process of Smac/DIABLO to XIAP and caspase release requires a conserved
tetrapeptide
A tetrapeptide is a peptide, classified as an oligopeptide, since it only consists of four amino acids joined by peptide bonds. Many tetrapeptides are pharmacologically active, often showing affinity and specificity for a variety of receptors in p ...
motif.
Clinical significance
Deregulation of XIAP can result in "
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
,
neurodegenerative disorder
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
s, and
autoimmunity
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
".
High proportions of XIAP may function as a
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
marker.
In the development of lung cancer NCI-H460, the overexpression of XIAP not only inhibits caspase, but also stops the activity of
cytochrome c (
Apoptosis). In developing
prostate cancer, XIAP is one of four IAPs overexpressed in the prostatic
epithelium, indicating that a molecule that inhibits all IAPs may be necessary for effective treatment.
Apoptotic regulation is an extremely important biological function, as evidenced by "the conservation of the IAPs from humans to ''Drosophila''".
Mutations in the XIAP gene can result in a severe and rare type of
inflammatory bowel disease.
[
*] Defects in the XIAP gene can also result in an extremely rare condition called
X-linked lymphoproliferative disease type 2.
Interactions
XIAP has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
ALS2CR2,
*
Caspase 3
Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are als ...
.
* Caspase 7
Caspase-7, apoptosis-related cysteine peptidase, also known as CASP7, is a human protein encoded by the ''CASP7'' gene.
''CASP7'' orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs ...
,
* Caspase-9
Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such ...
,
* Diablo homolog
Diablo homolog (DIABLO) is a mitochondrial protein that in humans is encoded by the ''DIABLO'' (direct IAP binding protein with low pI) gene on chromosome 12. DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC. ...
* HtrA serine peptidase 2
Serine protease HTRA2, mitochondrial is an enzyme that in humans is encoded by the ''HTRA2'' gene. This protein is involved in caspase-dependent apoptosis and in Parkinson's disease.
Structure Gene
The gene ''HTRA2'' encodes a serine protease. T ...
,
* MAGED1,
* MAP3K2,
* TAB1
Mitogen-activated protein kinase kinase kinase 7-interacting protein 1 is an enzyme that in humans is encoded by the ''TAB1'' gene.
Function
The protein encoded by this gene was identified as a regulator of the MAP kinase kinase kinase MAP3K7 ...
, and
* XAF1.
References
Further reading
*
*
External links
GeneReviews/NCBI/NIH/UW entry on Lymphoproliferative Disease, X-Linked
{{DEFAULTSORT:Xiap
Cell signaling
Programmed cell death
Apoptosis
EC 6.3.2