Sandbox Reserved 658

This Sandbox is Reserved from 30/08/2012, through 01/02/2013 for use in the course "Proteins and Molecular Mechanisms" taught by Robert B. Rose at the North Carolina State University, Raleigh, NC USA. This reservation includes Sandbox Reserved 636 through Sandbox Reserved 685.

To get started: Click the edit this page tab at the top. Save the page after each step, then edit it again. Click the 3D button (when editing, above the wikitext box) to insert Jmol. show the Scene authoring tools, create a molecular scene, and save it. Copy the green link into the page. Add a description of your scene. Use the buttons above the wikitext box for bold, italics, links, headlines, etc. More help: Help:Editing For more help, look at this link: http://proteopedia.org/w/Help:Getting_Started_in_Proteopedia Human Caspase 3Human Caspase 3 Caspase 3 is a member of the Cysteine dependent asparte directed protease (Caspase) family of proteins.It is found in vertebrates and is a highly conserved protein with about 60 percent sequence similirity in human, chicken, zebrafish, mouse etc. Caspase 3 plays an iportant role in programmed cell death or cell suicide " apoptosis". It functions by proteolyting the actin filaments of the cytoskeleton of the cells resulting in its collapse.This results in production of signals which calls for phagocytosis of the resulting cellular debris. Expression of caspase 3 is a tightly regulated process. ApoptosisApoptosis Every day billions of cells die in a human body and billions more are generated.It is essential that the total number of functional cells is kept constant in order to maintain homeostatis. While mitosis is resposible for the increased number of cells, programmed cell death is responsible for the removal of unwanted cells. The cells may undergo programmed cell death if it meets with adverse conditions such as stress, death signal or DNA damage.In multi cellular organisms the DNA damaged cells are removed so that the damaged DNA will not be inherited by progenitor cells.Programmed Cell death can be classified as Apoptosis and Autophagy. Apart from maintaining cellular homeostasis Apoptosis is involved in developmenta biology as well. For example in a developing human embryo the fingers are connected to each other by tissue that makes it look like the webbed feet of a duck. Apoptosis removes the tissues in between the fingers and the digits appear individual. it is also importand in neuronal development. Apoptosis in a cell is characterised by morphological changes such as blebbing, cell shrinking, nuclear fragmentation, chromatin condensation and chromosomal DNA fragmentation. Apoptosis in a cell is signalled by exrtinsic signalling pathway or intrinsic signalling pathway. Often, there is a crosstalk between the two pathways. spinqualitylabelsall models Caspase 3 monomer Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image CaspasesCaspases There are three types of caspases but in context of apoptosis, these two types are relevent. Initiator caspases: caspases 2, 8, 9 and 10. They are activated by various apopotic signal. They in turn activate the executioner caspases. Effector or executioner caspases: caspases 3, 6 and 7. They execute the final task of proteolysis. All the caspases have similar strudtures.Their monomers are composed of a prodomain and a big subunit and a small subunit. initiator caspases are stable monomers and are activated upon dimerization. Executioner caspases are stable dimer and have to undergo conformational change to be activated. Caspase 3Caspase 3 Caspase monomer is a 277 amino acid residue long polypeptide.It has a prodomain and a small subunit and a big subunit.It is a 35 Kilo Dalton protein.The sall sub unit is about 12 Kilo Daltons and the large subunit is about 17 kilo daltons. On SDS PADGE gel we can see the two different subunits on different lanes. The stable zymogen is a homodimer and is called procaspase. In the cell, the procaspase is in an equilibrium between active and inactive conformation with the latter being favoured. An active enzyme would be prodomain less.Each monomer consists of 6 beta sheets and 5 alfa helices making the dimer to contain 10 alfa helices and 12 beta sheets. Activation of Caspase 3Activation of Caspase 3 As mentioned earlier, caspase 3 is executioner caspase that is activated by initiater caspases 8 and 9. Conformational chanage is vital in the activation of caspase 3. This change is brought about by the removal of the pro domain and the cleavage of the intersubunit linker (IL).Il is a chain that connects the small subunit of the monomer with the big subunit. Also important is the dimer interface which has been found to act as an allosteric site. So, it is possible that the procaspase itself can be activated if suitable allosteric activators can be found. Mode of ActionMode of Action Caspase 3 cleaves the peptide bond that comes after the aspartate residue. The consensus tetrapeptide sequence -Asp-x-x-Asp- is recognized by caspase 3 in its substrates. The C- terminal Asp is essential whereas others can be replaced. The active site of caspase 3 is a highly conserved pentapeptide -Gln-Ala-Cys-Arg-Gly- (161 to 165). Cys 163 uses its sulfohydryl group to cleave the peptide bonds. Diseases that occur due to defects in regulation of caspase 3Diseases that occur due to defects in regulation of caspase 3 Overexpression and activation of caspase three leads to diseases such as autoimmune disorders, Alzeimers' disease , heart disease etc. Inability to express and activate caspase 3 leads to cancer as cells that have DNA damage cannot be removed via apoptosis. This makes caspase 3 an important targets for drug developing research. Scientists are working to find out ways to activate an d repress caspase 3 via drug administration as a method of treatment for aforementioned deadly diseases. ReferencesReferences 1.A bifunctional allosteric site in the dimer interface of procaspase-3 Joshua L. Schipper a, Sarah H. MacKenzie a, Anil Sharma b,1, A. Clay Clark a,⁎ a Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA b Department of Chemistry, North Carolina State University, Raleigh, NC 27695, USA 2.Wikipedia 3.Protein Data Bank