Phosphorylation

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A phosphorylated serine residue

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Phosphorylation is the addition of a phosphate (PO4) group to a protein molecule or a small molecule. Another way to define it would be the introduction of a phosphate group into an organic molecule. Its prominent role in biochemistry is the subject of a very large body of research (as of January 2006, the Medline database returns over 120,000 articles on the subject, largely on protein phosphorylation).

Protein phosphorylation

Function

In eukaryotes, protein phosphorylation can be an important regulatory event. Many enzymes and receptors are switched "on" or "off" by phosphorylation and dephosphorylation. Phosphorylation is catalyzed by various specific protein kinases, whereas phosphatases dephosphorylate.

Adding a phosphate (PO4) to a polar R group of an amino acid might not seem like it would do much to a protein, but it can actually turn a nonpolar hydrophobic protein into a polar and extremely hydrophilic molecule. Phosphorylation is observed on serine, threonine, and tyrosine residues in eukaryotes and histidine residues in prokaryotes.

An example of the important role that phosphorylation plays is the p53 tumor suppressor gene, which—when active—stimulates transcription of genes that suppress the cell cycle, even to the extent that it undergoes apoptosis. However, this activity should be limited to situations where the cell is damaged or physiology is disturbed. To this end, the p53 protein is extensively regulated. In fact, p53 contains more than 18 different phosphorylation sites.

Upon the deactivating signal, the protein becomes dephosphorylated again and stops working. This is the mechanism in many forms of signal transduction, for example the way in which incoming light is processed in the light-sensitive cells of the retina.

In some settings, the purpose of phosphorylation is to "activate" or "energize" a molecule, increasing its energy so it is able to participate in a subsequent reaction with a negative free-energy change. All kinases require a divalent metal ion such as Mg2+ or Mn2+ to be present, which stabilizes the high-energy bonds of the donor molecule (usually ATP or ATP derivative) and allows phosphorylation to occur.

In other instances, phosphorylation of a protein substrate can inhibit its activity (as when AKT phosphorylates the enzyme GSK-3). One common mechanism for phosphorylation-mediated enzyme inhibition was demonstrated in the tyrosine kinase called "src" (pronounced "sarc", see: Src (gene)). When src is phosphorylated on a particular tyrosine, it folds on itself, and thus masks its own kinase domain, and is thus shut "off".

In still other instances, phosphorylation of a protein causes it to be bound to other proteins which have "recognition domains" for a phosphorylated tyrosine, serine, or threonine motif. As a result of binding a particular protein, a distinct signaling system may be activated or inhibited.

In the late 1990s it was recognized that phosphorylation of some proteins causes them to be degraded by the ATP-dependent ubiquitin/proteasome pathway. These target proteins become substrates for particular E3 ubiquitin ligases only when they are phosphorylated.

Signaling networks

The network underlying phosphorylation can be very complex. In some cellular signalling pathways, a protein A phosphorylates B, and B phosphorylates C, but A also phosphorylates C directly, and B can phosphorylate D, which may in turn phosphorylate A. Global approaches to identify and quantify phosphorylated proteins, like mass spectrometry-based proteomics, are becoming increasingly important for the systematic analysis of complex phosphorylation networks. For example, one study has identified dynamic changes in the phosphorylation status of more than 6000 sites after stimulation with epidermal growth factor. Analysis of phosphoproteins is a branch of proteomics called phosphoproteomics.

Protein phosphorylation sites

There are thousands of distinct phosphorylation sites in a given cell since: 1) There are thousands of different kinds of proteins in any particular cell (such as a lymphocyte). 2) It is estimated that 1/10th to 1/2 of proteins are phosphorylated (in some cellular state). 3) Phosphorylation often occurs on multiple distinct sites on a given protein.

Since phosphorylation of any site on a given protein can change the function or localization of that protein, understanding the "state" of a cell requires knowing the phosphorylation state of its proteins. For example, if amino acid Serine-473 ("S473") in the protein AKT is phosphorylated AKT is generally functionally active as a kinase. If not, it is an inactive kinase.

Types of phosphorylation

See also protein kinase for more details on the different types of phosphorylation

Within a protein, phosphorylation can occur on several amino acids. Phosphorylation on serine is the most common, followed by threonine. Tyrosine phosphorylation is relatively rare. However, since tyrosine phosphorylated proteins are relatively easy to purify using antibodies, tyrosine phosphorylation sites are relatively well understood. Histidine and aspartate phosphorylation occurs in prokaryotes as part of two-component signalling.

Detection and characterization

Antibodies can be used as powerful tools to detect whether a protein is phosphorylated at any particular site. Such antibodies are called phospho-specific antibodies; hundreds of such antibodies are now available. They are becoming critical reagents both for basic research and for clinical diagnosis.

Example of posttranslational modification detected on a 2D gel (spot boundaries delimited by analysis software, identification by mass spectrometry , P46462 is the protein ID in Expasy)

PTM (Phospho-Tyrosine Modified) isoforms are easily detected on 2D gels. Indeed, phosphorylation replaces neutral hydroxyl groups on serines, threonines or tyrosines with negatively charged phosphates with pKs near 1.2 and 6.5. Thus, below pH 5.5, phosphates add a single negative charge, near pH 6.5 they add 1.5 negative charges and above pH 7.5 they add 2 negative charges. The relative amount of each isoform can also easily and rapidly be determined from staining intensity on 2D gels.

A detailed characterization of the sites of phosphorylation is very difficult and the quantitation of protein phosphorylation by mass spectrometry requires isotopic internal standard approaches (Gerber et al., 2003). A relative quantitation can be obtained with a variety of differential isotope labeling technologies (Gigy et al., 2002, Goshe et al., 2003).

History

In 1906, Phoebus A. Levene at the Rockefeller Institute for Medical Research identified phosphate in the protein Vitellin (phosvitin), and by 1933 had detected phosphoserine in Casein, with Fritz Lipmann. However, it took another 20 years before Eugene P. Kennedy described the first ‘enzymatic phosphorylation of proteins’.

Other kinds

ATP, the "high-energy" exchange medium in the cell, is synthesized in the mitochondrion by addition of a third phosphate group to ADP in a process referred to as oxidative phosphorylation. ATP is also synthesized by substrate-level phosphorylation during glycolysis. ATP is synthesized at the expense of solar energy by photophosphorylation in the chloroplasts of plant cells.

Phosphorylation of sugars is often the first stage of their catabolism. It allows cells to accumulate sugars because the phosphate group prevents the molecules from diffusing back across their transporter.

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Cost Effectiveness of Phosphorylation

| group5 = Clinical Trials Involving Phosphorylation | list5 = Ongoing Trials on Phosphorylation at Clinical Trials.govTrial results on PhosphorylationClinical Trials on Phosphorylation at Google


| group6 = Guidelines / Policies / Government Resources (FDA/CDC) Regarding Phosphorylation | list6 = US National Guidelines Clearinghouse on PhosphorylationNICE Guidance on PhosphorylationNHS PRODIGY GuidanceFDA on PhosphorylationCDC on Phosphorylation


| group7 = Textbook Information on Phosphorylation | list7 = Books and Textbook Information on Phosphorylation


| group8 = Pharmacology Resources on Phosphorylation | list8 = AND (Dose)}} Dosing of PhosphorylationAND (drug interactions)}} Drug interactions with PhosphorylationAND (side effects)}} Side effects of PhosphorylationAND (Allergy)}} Allergic reactions to PhosphorylationAND (overdose)}} Overdose information on PhosphorylationAND (carcinogenicity)}} Carcinogenicity information on PhosphorylationAND (pregnancy)}} Phosphorylation in pregnancyAND (pharmacokinetics)}} Pharmacokinetics of Phosphorylation


| group9 = Genetics, Pharmacogenomics, and Proteinomics of Phosphorylation | list9 = AND (pharmacogenomics)}} Genetics of PhosphorylationAND (pharmacogenomics)}} Pharmacogenomics of PhosphorylationAND (proteomics)}} Proteomics of Phosphorylation


| group10 = Newstories on Phosphorylation | list10 = Phosphorylation in the newsBe alerted to news on PhosphorylationNews trends on Phosphorylation


| group11 = Commentary on Phosphorylation | list11 = Blogs on Phosphorylation

| group12 = Patient Resources on Phosphorylation | list12 = Patient resources on PhosphorylationDiscussion groups on PhosphorylationPatient Handouts on PhosphorylationDirections to Hospitals Treating PhosphorylationRisk calculators and risk factors for Phosphorylation


| group13 = Healthcare Provider Resources on Phosphorylation | list13 = Symptoms of PhosphorylationCauses & Risk Factors for PhosphorylationDiagnostic studies for PhosphorylationTreatment of Phosphorylation

| group14 = Continuing Medical Education (CME) Programs on Phosphorylation | list14 = CME Programs on Phosphorylation

| group15 = International Resources on Phosphorylation | list15 = Phosphorylation en EspanolPhosphorylation en Francais

| group16 = Business Resources on Phosphorylation | list16 = Phosphorylation in the MarketplacePatents on Phosphorylation

| group17 = Informatics Resources on Phosphorylation | list17 = List of terms related to Phosphorylation


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