XIAP
Encyclopedia
X-linked inhibitor of apoptosis protein (XIAP) also known as inhibitor of apoptosis protein 3 (IAP3) and baculoviral IAP repeat-containing protein 4 (BIRC) is a protein
that in humans is encoded by the XIAP gene
.
XIAP is a member of the inhibitor of apoptosis
family of proteins (IAP). IAPs were initially identified in baculovirus
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.
was discovered at site Xq24-25. Using PCR and cloning
, three BIR domain
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.
. Secondly, there is a UBA domain, which allows XIAP to bind to ubiquitin
. 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.
s, the enzymes primarily responsible for cell death. XIAP binds to and inhibits caspase 3
, 7
and 9. The BIR2 domain of XIAP inhibits caspase 3 and 7, while BIR3 binds to and inhibits caspase 9. The RING domain utilizes E3 ubiquitin
ligase activity and enables IAPs to catalyze ubiquination of self, caspase-3, or caspase-7 by degradation via proteasome
activity. However, mutation
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
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, Fas, UV light, and genotoxic agents".
The second BIR domain of XIAP can be shown binding to caspase 3 where a protein substrate would normally bind during aptosis. By blocking this binding, XIAP inhibits apoptosis.
(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
motif.
, neurodegenerative disorders, and autoimmunity
”. High proportions of XIAP may function as a tumor
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
.
with:
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the XIAP gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
XIAP is a member of the inhibitor of apoptosis
Inhibitor of apoptosis
The Inhibitors of Apoptosis are a family of functionally- and structurally-related proteins, which serve as endogenous inhibitors of programmed cell death . A common feature of all IAPs is the presence of a BIR in one to three copies...
family of proteins (IAP). IAPs were initially identified in baculovirus
Baculovirus
The baculoviruses are a family of large rod-shaped viruses that can be divided to two genera: nucleopolyhedroviruses and granuloviruses . While GVs contain only one nucleocapsid per envelope, NPVs contain either single or multiple nucleocapsids per envelope. The enveloped virions are further...
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
BIRC2
Baculoviral IAP repeat-containing protein 2 is a protein that in humans is encoded by the BIRC2 gene.-Interactions:...
. 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 domainRING finger domain
In molecular biology, a RING finger domain is a protein structural domain of zinc finger type which contains a Cys3HisCys4 amino acid motif which binds two zinc cations. This protein domain contains from 40 to 60 amino acids...
was discovered at site Xq24-25. Using PCR and cloning
Cloning
Cloning in biology is the process of producing similar populations of genetically identical individuals that occurs in nature when organisms such as bacteria, insects or plants reproduce asexually. Cloning in biotechnology refers to processes used to create copies of DNA fragments , cells , or...
, three BIR domain
Inhibitor of apoptosis 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...
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 IAPIAP
IAP is an initialism or acronym which can mean:* Identical ancestors point, a point in time in the past where every living member of a species at that time is either an ancestor to all living of that species or none living....
. Secondly, there is a UBA domain, which allows XIAP to bind to ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
. 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.
Function
XIAP stops apoptotic cell death induced either by viral infection or by overproduction of caspaseCaspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
s, the enzymes primarily responsible for cell death. XIAP binds to and inhibits caspase 3
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...
, 7
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...
and 9. The BIR2 domain of XIAP inhibits caspase 3 and 7, while BIR3 binds to and inhibits caspase 9. The RING domain utilizes E3 ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
ligase activity and enables IAPs to catalyze ubiquination of self, caspase-3, or caspase-7 by degradation via proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
activity. However, mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s affecting the RING Finger do not significantly affect apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, 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
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
, which is released into the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
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, Fas, UV light, and genotoxic agents".
The second BIR domain of XIAP can be shown binding to caspase 3 where a protein substrate would normally bind during aptosis. By blocking this binding, XIAP inhibits apoptosis.
Inhibiting XIAP
XIAP is inhibited by DIABLODiablo homolog
Diablo homolog, mitochondrial is a protein that in humans is encoded by the DIABLO gene . DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC.- Function :...
(Smac) and HTRA2
HtrA serine peptidase 2
Serine protease HTRA2, mitochondrial is an enzyme that in humans is encoded by the HTRA2 gene.-Interactions:HtrA serine peptidase 2 has been shown to interact with MAPK14, XIAP and BIRC2.-External Links:...
(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
Tetrapeptide
A tetrapeptide is a peptide consisting of four amino acids joined by peptide bonds. Many tetrapeptides are pharmacologically active, often showing affinity and specificity for a variety of receptors in protein-protein signaling...
motif.
Clinical significance
Deregulation of XIAP can result in “cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, neurodegenerative disorders, and autoimmunity
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
”. High proportions of XIAP may function as a tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
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
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
(Apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
). In developing prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
, XIAP is one of four IAPs overexpressed in the prostatic epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
, 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
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
. Defects in the XIAP gene can also result in an extremely rare condition called X-linked lymphoproliferative disease
X-linked lymphoproliferative disease
X-linked lymphoproliferative disease is a lymphoproliferative disorder.-XLP1:There is a mutation on the X-chromosome that has been found to be associated with a T- and NK-cell lymphoproliferative disorder. The mutation is on the long arm of the chromosome, at position 25, which is denoted as Xq25...
.
Interactions
XIAP has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- ALS2CR2ALS2CR2STE20-related kinase adapter protein beta is an enzyme that in humans is encoded by the STRADB gene.-Further reading:...
, - Caspase 3Caspase 3Caspase 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...
. - Caspase 7Caspase 7Caspase-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...
, - Caspase-9Caspase-9Caspase-9 is an initiator caspase, encoded by the CASP9 gene.CASP9 orthologs have been identified in all mammals for which complete genome data are available. Unique orthologs are also present in lizards, lissamphibians, and teleosts....
, - Diablo homologDiablo homologDiablo homolog, mitochondrial is a protein that in humans is encoded by the DIABLO gene . DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC.- Function :...
- HtrA serine peptidase 2HtrA serine peptidase 2Serine protease HTRA2, mitochondrial is an enzyme that in humans is encoded by the HTRA2 gene.-Interactions:HtrA serine peptidase 2 has been shown to interact with MAPK14, XIAP and BIRC2.-External Links:...
, - MAGED1MAGED1Melanoma-associated antigen D1 is a protein that in humans is encoded by the MAGED1 gene.-Interactions:MAGED1 has been shown to interact with UNC5A, PJA1 and XIAP.-Further reading:...
, - MAP3K2MAP3K2Mitogen-activated protein kinase kinase kinase 2 is an enzyme that in humans is encoded by the MAP3K2 gene.-Interactions:MAP3K2 has been shown to interact with SH2D2A, MAP2K7, MAP2K5, XIAP and MAPK8.-Further reading:...
, - MAP3K7IP1MAP3K7IP1Mitogen-activated protein kinase kinase kinase 7-interacting protein 1 is an enzyme that in humans is encoded by the MAP3K7IP1 gene.This protein plays an important role in skin homeostasis, wound repair, and oncogenesis.-Interactions:...
, and - XAF1XAF1XIAP-associated factor 1 is a protein that in humans is encoded by the XAF1 gene.-Further reading:...
.