Survivin

1E31, 1F3H, 1XOX, 2QFA, 2RAW, 2RAX, 3UEC, 3UED, 3UEE, 3UEF, 3UEG, 3UEH, 3UEI, 3UIG, 3UIH, 3UII, 3UIJ, 3UIK, 4A0I, 4A0J, 4A0N33211799ENSG00000089685ENSMUSG00000017716O15392O70201NM_001012270NM_001012271NM_001168NM_001012272NM_001012273NM_009689NP_001012270NP_001012271NP_001159NP_001012273NP_033819Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the BIRC5 gene. NCBI Reference Sequence: NG_029069.11e31: SURVIVIN DIMER H. SAPIENS1f3h: X-RAY CRYSTAL STRUCTURE OF THE HUMAN ANTI-APOPTOTIC PROTEIN SURVIVIN1xox: SOLUTION STRUCTURE OF HUMAN SURVIVIN Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the BIRC5 gene. NCBI Reference Sequence: NG_029069.1 Survivin is a member of the inhibitor of apoptosis (IAP) family. The survivin protein functions to inhibit caspase activation, thereby leading to negative regulation of apoptosis or programmed cell death. This has been shown by disruption of survivin induction pathways leading to increase in apoptosis and decrease in tumour growth. The survivin protein is expressed highly in most human tumours and fetal tissue, but is completely absent in terminally differentiated cells. These data suggest survivin might provide a new target for cancer therapy that would discriminate between transformed and normal cells. Survivin expression is also highly regulated by the cell cycle and is only expressed in the G2-M phase. It is known that Survivin localizes to the mitotic spindle by interaction with tubulin during mitosis and may play a contributing role in regulating mitosis. The molecular mechanisms of survivin regulation are still not well understood, but regulation of survivin seems to be linked to the p53 protein. It also is a direct target gene of the Wnt pathway and is upregulated by beta-catenin. Survivin is a member of the IAP family of antiapoptotic proteins. It is shown to be conserved in function across evolution as homologues of the protein are found both in vertebrates and invertebrates. The first members of the IAPs identified were from the baculovirus IAPs, Cp-IAP and Op-IAP, which bind to and inhibit caspases as a mechanism that contributes to its efficient infection and replication cycle in the host. Later, five more human IAPs that included XIAP, c-IAPl, C-IAP2, NAIP, and survivin were discovered. Survivin, like the others, was discovered by its structural homology to IAP family of proteins in human B-cell lymphoma. The human IAPs, XIAP, c-IAPl, C-IAP2 have been shown to bind to caspase-3 and -7, which are the effector caspases in the signaling pathway of apoptosis. It is not known with absolute certainty though, how the IAPs inhibit apoptosis mechanistically at the molecular level. A common feature that is present in all IAPs in the presence of a BIR (Baculovirus IAP Repeat, a ~70 amino acid motif) in one to three copies. It was shown by Tamm et al. that knocking out BIR2 from XIAP was enough to cause a loss of function in terms of XIAPs ability to inhibit caspases. This gives the implication that it is within these BIR motifs that contains the anti-apoptotic function of these IAPs. Survivin's one BIR domain shows a similar sequence compared to that of XIAP's BIR domains. The single survivin gene can give rise to four different alternatively spliced transcripts: A structural feature common to all IAP family proteins is that they all contain at least one baculoviral IAP repeat (BIR) domain characterized by a conserved zinc-coordinating Cys/His motif at the N-terminal half of the protein. Survivin is distinguished from other IAP family members in that it has only one BIR domain. The mice and human BIR domain of survivin are very similar structurally except for two differences that may affect function variability. The human survivin also contains an elongated C-terminal helix comprising 42 amino acids. Survivin is 16.5 kDa large and is the smallest member of the IAP family.X-ray crystallography has shown two molecules of human surviving coming together to form a bowtie-shape dimer through a hydrophobic interface. This interface includes N-terminal residues 6-10 just before the BIR domain region and the 10 residue region connecting the BIR domain to the C-terminal helix. The structural integrity of the determined crystal structure of survivin is quite reliable, as physiological conditions were used to obtain the images. Apoptosis, the process of programmed cell death, involves complex signaling pathways and cascades of molecular events. This process is needed for proper development during embryonic and fetal growth where there is destruction and reconstruction of cellular structures. In adult organisms, apoptosis is needed to maintain differentiated tissue by striking the balance between proliferation and cell death. It is known that intracellular proteases called caspases degrade the cellular contents of the cell by proteolysis upon activation of the death pathway.