User:Ivicentelare2020/Scaffold protein

= Scaffold protein = From Wikipedia, the free encyclopedia

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In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them into complexes. In such pathways, they regulate signal transduction, they join interacting proteins and help localize pathway components (organized in complexes) to specific areas of the cell such as the plasma membrane, the cytoplasm, the nucleus, the Golgi, endosomes, and the mitochondria.

Contents

 * 1History
 * 2Function
 * 2.1Tethering signaling components
 * 2.2Localization of signaling components in the cell
 * 2.3Coordinating positive and negative feedback
 * 2.4Insulating correct signaling proteins from inactivation
 * 3Scaffold protein summary
 * 4Huntingtin protein
 * 5Other usage of the term Scaffold Protein
 * 6References

History[edit]
The first signaling scaffold protein discovered was the Ste5 protein from the yeast Saccharomyces cerevisiae. Three distinct domains of Ste5 were shown to associate with the protein kinases Ste11, Ste7, and Fus3 to form a multikinase complex.

Function[edit]
Scaffold proteins act in at least four ways: tethering signaling components, localizing these components to specific areas of the cell, regulating signal transduction by coordinating positive and negative feedback signals, and insulating correct signaling proteins from competing proteins.

Tethering signaling components[edit]
This particular function is considered a scaffold's most basic function. Scaffolds assemble signaling components of a cascade into complexes. This assembly may be able to enhance signaling specificity by preventing unnecessary interactions between signaling proteins, and enhance signaling efficiency by increasing the proximity and effective concentration of components in the scaffold complex. A common example of how scaffolds enhance specificity is a scaffold that binds a protein kinase and its substrate, thereby ensuring specific kinase phosphorylation. Additionally, some signaling proteins require multiple interactions for activation and scaffold tethering may be able to convert these interactions into one interaction that results in multiple modifications. Scaffolds may also be catalytic as interaction with signaling proteins may result in allosteric changes of these signaling components. Such changes may be able to enhance or inhibit the activation of these signaling proteins. An example is the Ste5 scaffold in the mitogen-activated protein kinase (MAPK) pathway. Ste5 has been proposed to direct mating signaling through the Fus3 MAPK by catalytically unlocking this particular kinase for activation by its MAPKK Ste7.

Localization of signaling components in the cell[edit]
Scaffolds localize the signaling reaction to a specific area in the cell, a process that could be important for the local production of signaling intermediates. A particular example of this process is the scaffold, A-kinase anchor proteins (AKAPs), which target cyclic AMP-dependent protein kinase (PKA) to various sites in the cell. This localization is able to locally regulate PKA and results in the local phosphorylation by PKA of its substrates.

Coordinating positive and negative feedback[edit]
Many hypotheses about how scaffolds coordinate positive and negative feedback come from engineered scaffolds and mathematical modeling. In three-kinase signaling cascades, scaffolds bind all three kinases, enhancing kinase specificity and restricting signal amplification by limiting kinase phosphorylation to only one downstream target. These abilities may be related to stability of the interaction between the scaffold and the kinases, the basal phosphatase activity in the cell, scaffold location, and expression levels of the signaling components.

Insulating correct signaling proteins from inactivation[edit]
Signaling pathways are often inactivated by enzymes that reverse the activation state and/or induce the degradation of signaling components. Scaffolds have been proposed to protect activated signaling molecules from inactivation and/or degradation. Mathematical modeling has shown that kinases in a cascade without scaffolds have a higher probability of being dephosphorylated by phosphatases before they are even able to phosphorylate downstream targets. Furthermore, scaffolds have been shown to insulate kinases from substrate- and ATP-competitive inhibitors.

Structure
These proteins have rigid scaffolds on one extreme and flexible ones on the other.

added
Scaffold proteins are key hubs of information downstream of activated GPCRs. Scaffold proteins recruit downstream members of a signaling cascade to the inner cell membrane very quickly, or ahead of time, making it efficient for the message to move from GPCR to cytosol.

Scaffold proteins help relay the message between the cell membrane and nucleus faster. They do this by serving as a docking site for multiple protein partners in the cascade so they can be near each other. This proximity cuts down the time required for one protein in the cascade to find its partner. Some protein scaffolds remain unloaded until a message from an activated membrane receptor reaches them, after which they are docked by several proteins in the cascade. Other protein scaffolds are docked by proteins in the cascade even before an activated membrane receptor sends a message to them, increasing the efficiency in which the message is relayed from receptor to nucleus.

The name “scaffold” implies the formation of a stable complex, a notion further reinforced by their highly specific localizations. However, over the past decade, there have been examples of scaffolding protein complexes long thought to provide stable linkages but subsequently found to be surprisingly dynamic. These advances have been driven by the increased accessibility of techniques such as FRAP (fluorescence recovery after photobleaching) and photoactivation to examine the dynamics of components in vivo. Despite these advances, the in vivo dynamics of many scaffold complexes are often not considered.

Scaffolds also perform critical roles in cell polarity (Thompson, 2013). The scaffold Bem1 coordinates a feedback loop to generate localized activation of Cdc42 to ensure that budding yeast assembles a single bud (Johnson et al., 2011). The PDZ scaffolds par-3 and par-6 are essential for establishment of asymmetry and proper cleavage in the early embryo of Caenorhabditis elegans (Kemphues et al., 1988; Watts et al., 1996). In Drosophila, Scrib (scribble), Dlg (discs large), Baz (Bazooka), and Sdt (stardust) are all PDZ scaffolds that regulate epithelial polarity (Woods and Bryant, 1991; Bilder et al., 2003). Another PDZ scaffold, ZO-1 (zona occludens-1) is involved in the stabilization and barrier function of tight junctions (Stevenson et al., 1986). Additionally, the linking proteins α- and β-catenin play vital roles in cadherin-based cell–cell adhesion, which helps give rise to the functional organization of cells into tissues (Ozawa et al., 1989; Gumbiner, 2000). The overwhelming majority of these scaffolds involved in polarity are highly conserved across species, further highlighting their importance.

Although various signaling pathways are the central topics in many biological fields, researchers pay much less attention on the scaffold proteins. One possible reason is that identification of scaffold proteins is challenging, which requires multiple steps using traditional biochemical techniques, including selection of a candidate scaffold protein, testing the protein-protein interaction and assessment of the signaling pathway. The systematic study of scaffold proteins can greatly enhance the understanding of the protein regulation that occurs in eukaryotic organisms.

Huntingtin protein[edit]
Huntingtin protein co-localizes with ATM repair protein at sites of DNA damage. Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex. Huntington’s disease patients with aberrant huntingtin protein are deficient in repair of oxidative DNA damage. Oxidative DNA damage appears to underlie Huntington’s disease pathogenesis. Huntington’s disease is likely caused by the dysfunction of mutant huntingtin scaffold protein in DNA repair leading to increased oxidative DNA damage in metabolically active cells.