XIAP

X-linked Inhibitor of Apoptosis Protein (XIAP) is a member of the Inhibitor of apoptosis family of proteins (IAP). IAPs were initially identified in baculoviruses, but XIAP is one of the homologous proteins found in mammals.cite journal | author = Holcik M, Korneluk RG | title = Functional characterization of the X-linked inhibitor of apoptosis (XIAP) internal ribosome entry site element: role of La autoantigen in XIAP translation | journal = Mol. Cell. Biol. | volume = 20 | issue = 13 | pages = 4648–57 | year = 2000 | month = July | pmid = 10848591 | pmc = 85872 | doi = 10.1128/MCB.20.13.4648-4657.2000 | url = | issn = ] 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.cite journal | author = Deveraux QL, Reed JC | title = IAP family proteins – suppressors of apoptosis | journal = Genes Dev. | volume = 13 | issue = 3 | pages = 239–52 | year = 1999 | month = February | pmid = 9990849 | doi = 10.1101/gad.13.3.239 | url = | issn = ]

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, three BIR domains 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, like the rest of the IAP family, has two major structural elements. Firstly, there is the baculoviral IAP repeat (BIR) domain consisting of approximately 70 amino acids. Secondly, there is a zinc-binding domain, or a “carboxy-terminal RING Finger”.cite journal | author = Duckett CS, Li F, Wang Y, Tomaselli KJ, Thompson CB, Armstrong RC | title = Human IAP-like protein regulates programmed cell death downstream of Bcl-xL and cytochrome c | journal = Mol. Cell. Biol. | volume = 18 | issue = 1 | pages = 608–15 | year = 1998 | month = January | pmid = 9418907 | pmc = 121528 | url = http://mcb.asm.org/cgi/content/abstract/18/1/608 | issn = ] XIAP has been characterized with three amino-terminal BIR domains and 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.cite journal | author = Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H | title = Structural basis of caspase inhibition by XI
journal = Cell | volume = 104 | issue = 5 | pages = 781–90 | year = 2001 | month = March | pmid = 11257231 | doi = 10.1016/S0092-8674(01)00273-2 | url = | issn = ]

Function

XIAP stops apoptotic cell death induced either by viral infection or by overproduction of caspases, the enzymes primarily responsible for cell death. XIAP binds to and inhibits caspase 3, 7 and 9.cite journal | author = Deveraux QL, Takahashi R, Salvesen GS, Reed JC | title = X-linked IAP is a direct inhibitor of cell-death proteases | journal = Nature | volume = 388 | issue = 6639 | pages = 300–4 | year = 1997 | month = July | pmid = 9230442 | doi = 10.1038/40901 | url = | issn = ] 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, mutations 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.cite journal | author = Eckelman BP, Salvesen GS, Scott FL | title = Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family | journal = EMBO Rep. | volume = 7 | issue = 10 | pages = 988–94 | year = 2006 | month = October | pmid = 17016456 | pmc = 1618369 | doi = 10.1038/sj.embor.7400795 | url = | issn = ]

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.

Inhibiting XIAP

XIAP is inhibited by Smac/DIABLO and Omi/HtrA2, 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.cite web | url = http://www.celldeath.de/encyclo/aporev/apointro.pdf | title = Introduction to Apoptosis | author = Gewies A | authorlink = | coauthors = | date = 2003 | format = | work = | publisher = CellDeath.de | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-08-12]

Significance

Deregulation of XIAP can result in “cancer, neurodegenerative disorders, and autoimmunity”.cite journal | author = Wilkinson JC, Cepero E, Boise LH, Duckett CS | title = Upstream regulatory role for XIAP in receptor-mediated apoptosis | journal = Mol. Cell. Biol. | volume = 24 | issue = 16 | pages = 7003–14 | year = 2004 | month = August | pmid = 15282301 | pmc = 479745 | doi = 10.1128/MCB.24.16.7003-7014.2004 | url = | issn = | accessdate = 2008-08-12] 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.cite journal | author = Watson RW, Fitzpatrick JM | title = Targeting apoptosis in prostate cancer: focus on caspases and inhibitors of apoptosis proteins | journal = BJU Int. | volume = 96 Suppl 2 | issue = | pages = 30–4 | year = 2005 | month = December | pmid = 16359436 | doi = 10.1111/j.1464-410X.2005.05944.x | url = | issn = | accessdate = 2008-08-12] Apoptotic regulation is an extremely important biological function, as evidenced by "the conservation of the IAPs from humans to "Drosophila".cite journal | author = Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, Farahani R, McLean M, Ikeda JE, MacKenzie A, Korneluk RG | title = Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes | journal = Nature | volume = 379 | issue = 6563 | pages = 349–53 | year = 1996 | month = January | pmid = 8552191 | doi = 10.1038/379349a0 | url = | issn = | accessdate = 2008-08-12]

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Lacasse EC, Kandimalla ER, Winocour P, "et al." |title=Application of XIAP antisense to cancer and other proliferative disorders: development of AEG35156/ GEM640. |journal=Ann. N. Y. Acad. Sci. |volume=1058 |issue= |pages= 215–34 |year= 2006 |pmid= 16394139 |doi= 10.1196/annals.1359.032
*cite journal | author=Eckelman BP, Salvesen GS, Scott FL |title=Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. |journal=EMBO Rep. |volume=7 |issue= 10 |pages= 988–94 |year= 2006 |pmid= 17016456 |doi= 10.1038/sj.embor.7400795

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