Turnover Mechanisms

The Bovine herpsvirus 1 (BoHV-1) produces the protein UL49.5, which also interferes with the transport of peptides via TAP [13]. The BoHV-1 UL49.5 interacts with the TAP core particle, through its transmembrane domain and ER-luminal domain, and prevents rearrangements in the structure of TAP. These rearrangements typically occur subsequent to the binding of antigenic peptides and ATP. Such rearrangements influence the movement of TAP, as during peptide transport the transporter molecules move slower than those not bound to peptides. However, the binding of UL49.5 hinders such changes in TAP mobility by preventing structural rearrangements, which are essential for the translocation of peptides. BoHV-1 UL49.5 also interrupts peptide transport through promoting the degradation of the TAP1 and TAP2 subunits. This is achieved by the C-terminal cytoplasmic tail of UL49.5 which connects the TAP and UL49.5 complex to ubiquitin, thereby targeting it for proteasome mediated degradation [12, 13]. This transporter is also a key target for other viral evasion proteins (Table

Proteins are the metabolic workhorses of the cell; they engage in a variety of essential activities ranging from enzymatically catabolizing macromolecular food sources to serving as structural components that maintain cell stability. Maximizing protein function relies on intricate non-covalent interactions occurring on the secondary, tertiary, and quaternary levels that help determine the overall shape of the protein. In their native states, proteins will assume the most energetically favorable configuration. Occasionally however, cells are exposed to exogenous disruptions such as heat stress. Heat Stress can compromise protein three-dimensional structure. Hydrophobic residues tend to be buried in the interior of the protein but when

The GLAT enzyme itself belongs to the histidine triad super family and is a member of branch III. This enzyme shows specific nucleoside monophosphate activity and is a homodimer with each monomer containing a single domain comprised of 6 α- helices and a β-sheet which is formed by 13 antiparallel and 1 parallel strand. The mechanism of this enzyme is described as having ping-pong kinetics with the following two steps. In the first step the active site histidine attacks R-phosphorus of UDP-glucose which displaces glucose-1-phosphate and forms a covalent intermediate. The second step involves the previously formed intermediate reacting with galactose-1-phosphate to displace the histidine and produce UDP-galactose. (Facchiano, 103-104).

The high concentration of urea might unfold proteins because urea is a very good hydrogen donor and hydrogen acceptor. Urea molecules are basically able to fit in between hydrogen bonds and eventually destabilize the structures of the proteins.

al. 2006). When too much Ubiquinone were produced, and not enough electrons are transferred fast enough to form ubiquinol, the excessive Ubiquinone can oxidize TEO to oxaloacetate (OAA) . OAA then inhibits succinate oxidation. TEO binds to FAD functions to inhibit in the form of Oxaloacetate the flavin protein from taking hydrogen from succinate. In another sense TEO can be present and be inactive unless it was oxidized to OAA. OAA inhibits FAD from regular function (Muller FL, et al. 2007). This exergonic oxidation of malate by ubiquinone contributes to the driving force for loading the enzyme with OAA.

The protein usually targets old, dysfunctional proteins from the cell cycle, which makes sense for controlled cell division. The ubiquitination mechanism was originally obscure, but made more clear in the mid-1980’s by Aaron Ciechhanover, Avram Hershko, and Irwin Rose, which helped them win the Nobel Prize for Chemistry in 2004 (Nobel Prize website). Initially, the process was looked at as proteolytic system utilizing ATP. Many ATP-dependent proteolysis factor 1 (APF-1) molecules linked with a substrates that were later found to be deteriorated with free APF-1 in the cellular extract (Ciechhanover, 2012). APF-1 was called ubiquitin and it uses its C-terminal glycine to conjugate to the substrate’s

Hsp90 is a cytoplasmic protein which is globular in structure, being predominantly polar outside and nonpolar inside. Hsp90 can be activated through the binding with ATP where it has a specific ATP-binding site. It contains two conformational states, an open ATP-bound state and a closed ADP-bound state. There are three functional domains in Hsp90. There is the N-terminus binding domain where ATP-binding occurs, the

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The de-ubiquitinase (DUB) will cleave this precursor into free monomer ubiquitin molecules and can be activated and attached to the target protein through ATP dependent process called ubiquitination with the help of activating enzyme E1, conjugating enzyme E2, and ligase E3. Through forming (iso)-peptide, thioester, or ester bond between carboxyl groups of C-terminal glycine 76 on ubiquitin and the ε-amino group of the lysine, cysteine, serine/threonine on the substrate, respectively, the poly-ubiquitin chain is formed [3]. Based on the different internal Lysine (Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, and Lys63) and on the proximal ubiquitin, the (iso)-peptide bond can be form with another ubiquitin, distal mono-ubiquitin [4, 5]. Consequently, seven conventional poly-ubiquitin chains resulting in different 3-dimentional shapes explaining its different characteristics inherited upon binding to the target protein [5, 6]. With ranging more than 500 putative E3 ligases exist in human, the E3 ligase will tag the poly-ubiquitin chain to the target protein with high specificity

as catalytic role (Stassen et al., 1995; Laible et al., 1997). Moreover, these proteins share a similar

Proteins are complex macromolecules which are essential for life of all organisms. They are manufactured through the processes of transcription and translation, which take place inside the cells. More specifically, they are synthesised by ribosomes (Shakhnovich, 2007). Figure 1.1 shows the overall processes that can occur in making a fully functionally active protein. (Ghelis, 2012). Functional properties of certain proteins include, but is not limited to: structural composition of the cytoskeleton in cells, catalysing biochemical reactions and hormones such as insulin to regulate blood sugar concentration (O’Connor & Adams, 2014). Proteins must therefore have a specific 3-dimentional shape to allow them to carry out these functions. If their

Proteins themselves are made of long chains consisting of a possible 20 different amino acids that are linked together by peptide bonds made up by the hundreds or thousands for each different protein. These different combinations of chains determine the specific protein’s function and 3-D structure. A large percentage of work that is put into every cell is the result of proteins, as well as many crucial factors of the body, such as functioning organs. Proteins are not sectioned to perform any certain one function, but instead are responsible in varying areas all throughout the body. Enzymes, antibodies, cell structure, along with a multitude of other tasks, are the product of the many types of proteins working in synergy. Proteins have 4

Enzymes are specialized protein structures that increase the rate of reactions without changing chemical equilibrium between reactants and products (Cooper, 2000). These enzymes have a distinct chemical composition that constructs an active site for substrates to bind to; this is the location where the substances come together to from an enzyme-substrate complex, which makes forming a product possible. The shape of the molecule is extremely important to its function. Enzymes are composed of unique three-dimensional conformations, due to the complex folding during the secondary, tertiary, and

Research shows the cost of turnover is substantial and varies from region to region. The measurement of what costs are included are just as diverse, but according to Jones and Gates (2007), the cost of turnover can be 1.3 times a departing nurse’s salary. With this in mind, the costs of recruitment and retention cannot be underestimated nor seen as an expense, rather a return on investment.

Proteostasis is the way that organisms maintain protein fidelity in the body(Labbadia et al., 2015). It consists of multiple different mechanisms which help to coordinate protein synthesis, folding, disaggregation, and degradation(Labbadia et al., 2015). The multiple mechanisms that help to achieve proteostasis make up a system called the proteostasis network. This network incorporates all of the processes of proteostasis, including all machinery including translation, molecular chaperones, co-chaperones, the ubiquitin-proteome system, and the autophagy system(Labbadia et al., 2015). The unfolded protein response in the cytoplasm, endoplasmic reticulum, and mitochondria are not considered to be a direct part of the proteostasis network, however.