Enzymes perform numerous tasks in order to contribute to the global goal of organism survival. One such enzyme is Survivin. Survivin wears many “hats” within the cell and is a vital part of cellular homeostasis. Here I will introduce you to two of the main processes Survivin regulates.
Survivin is a multifunctional protein involved in mitotic division, cell survival and cancer progression. Sub cellular transcripts reveal the presence of four immunochemically distinct isoforms. Each isoform is hypothesized to perform distinct and overlapping tasks depending on location within the cell. It is expressed in dividing tissue but is noticeably absent from terminally differentiated tissue. Cancerous cells have an abundance of Survivin to ensure progression. Medical practitioners use survivin as an indicator of aggressiveness of a given cancer. This protein exists as a dimer and adopts a “bow-tie” shape upon dimerization; two hydrophobic anti-parallel beta sheets of each monomer are responsible for the dimer association. The N-terminal region is dominated by a BIR (Baculovirus Inhibitor of apoptosis Repeat) domain, while the C-terminus is an extended alpha helix (originally thought to be dimerization domain) (Fig 1.). Survivin is modulated by the addition of a phosphate group by kinases cdk1 and Aurora-β. These post-translational modifications increase association with other proteins and allow Survivin to resist proteasome degradation.
During mitotic division, it is essential that two distinct daughter cells are created with two distinct nuclei. Without Survivin, the cell is not able to delineate the two halves of the parental cell. Knockout studies of Survivin reveal embryonic lethality. In order to correctly divide and avoid polyploidy as well as an early onset of death, Survivin must associate with other chromosomal passenger proteins to coordinate proper division. The chromosomal passengers are bound to the centromeres and microtubules via their C-terminal extended alpha helices.
During apoptosis, extracellular or internal signals initiate a cascade of cell deconstruction. Cell death via these pathways is reliant on a group of enzymes called caspases. Caspases are regulated in a variety of ways, one of which is through Survivin. Survivin possesses the ability to block the function of pro-apoptotic bodies released during intrinsic apoptosis, Smac/Diablo is one such enzyme, and interacts through a binding event via the BIR domain. Smac/Diablo binds to XIAP (apoptosis inhibitor protein) which propagates an apoptosis signal. Survivin binds to Smac/Diablo, thus preventing this interaction from occurring. Therefore a cell exhibiting high levels of Survivin will be resistant to intrinsic apoptotic signals. Additionally, it has been shown that different isoforms of Survivin possess distinct abilities when it comes to regulating apoptosis. While one isoform, ∆Ex3, is responsible for the regulation of intrinsic apoptosis, isoform 2B is shown to block extrinsic signals (Fig 2). It remains unclear how isoform 2B accomplishes apoptosis resistance at this time.
The multifunctional roles of Survivin cast light onto a fact that is becoming ever more apparent in the field of biochemistry. Enzymes should not be viewed as stringent machines hell bent on a single job. Enzymes can be regulated, modulated and their genes spliced to perform various tasks in the cell. The plasticity of enzymes has always amazed me, and I hope you find this blog worth the read as well as informative.
- Johnson M.E. (2004). Survivin: A Bifunctional Inhibitor of Apoptosis Protein, Veterinary Pathology, 41 (6) 599-607. DOI: http://dx.doi.org/10.1354/vp.41-6-599
- WHEATLEY S. (2005). Survivin: A Protein with Dual Roles in Mitosis and Apoptosis, International Review of Cytology, 247 35-88. DOI: http://dx.doi.org/10.1016/s0074-7696(05)47002-3
- Tazo Y., Takashi Onda & Makoto Saegusa (2014). Bifunctional roles of survivin-ΔEx3 and survivin-2B for susceptibility to apoptosis in endometrial carcinomas, Journal of Cancer Research and Clinical Oncology, DOI: http://dx.doi.org/10.1007/s00432-014-1762-8