Protein Phosphorylation and Kinases
Protein phosphorylation, the reversible addition of a phosphate group to a protein, is one of the most widespread mechanisms by which cells control protein activity, localisation, and interactions. Protein kinases catalyse the transfer of phosphate from ATP onto specific serine, threonine, or tyrosine residues, while protein phosphatases remove it, together forming a reversible molecular switch central to signal transduction.
Definition
Protein phosphorylation is the enzyme-catalysed, reversible transfer of a phosphate group from ATP to specific amino-acid residues of a target protein by protein kinases, which is reversed by protein phosphatases, thereby modulating the target protein's function.
Scope
The topic covers the chemistry and regulation of protein phosphorylation, the major kinase families (serine/threonine and tyrosine kinases), their opposing phosphatases, and the role of this switch in relaying and integrating signals. It is treated as a biochemical and molecular subject within signal transduction.
Core questions
- How does phosphorylation change a protein's activity or interactions?
- How do kinases recognise their correct substrates?
- How is the balance between kinase and phosphatase activity controlled?
Key concepts
- Serine/threonine kinases
- Tyrosine kinases
- Protein phosphatases
- ATP as phosphate donor
- Substrate specificity and consensus motifs
- Reversible molecular switch
- The kinome
Mechanisms
A protein kinase binds ATP and a substrate protein and transfers the gamma-phosphate of ATP onto a hydroxyl-bearing residue, serine or threonine for the largest group of kinases and tyrosine for the tyrosine kinases. The added phosphate, being bulky and negatively charged, alters the local conformation of the substrate or creates a docking site for partner proteins, thereby switching the substrate's activity on or off. Phosphatases catalyse the reverse reaction, so the phosphorylation state of a protein reflects the balance of opposing kinase and phosphatase activities. Many kinases are themselves regulated by phosphorylation, allowing them to be organised into cascades. The human genome encodes a large family of kinases, collectively the kinome, that confers specificity through distinct substrate-recognition sequences and subcellular localisation.
Clinical relevance
Dysregulated kinase activity contributes to cancer and other diseases, and protein kinases are a major class of drug targets; receptor tyrosine kinases in particular are central to growth-factor signalling. This entry describes the underlying biochemistry at a reference level and is not a basis for individual diagnostic or treatment decisions.
Evidence & guidelines
The topic is grounded in enzymology, structural biology, and genomics, supported by primary research and authoritative reviews and textbooks rather than clinical practice guidelines.
History
Edwin Krebs and Edmond Fischer's mid-1950s discovery that glycogen phosphorylase is activated by phosphorylation established reversible phosphorylation as a regulatory mechanism, work recognised by a Nobel Prize. The later identification of tyrosine phosphorylation and of receptor tyrosine kinases extended the concept to growth-factor signalling, and the systematic cataloguing of the human kinome placed the kinase families in a genome-wide framework.
Key figures
- Edwin Krebs
- Edmond Fischer
- Tony Hunter
- Joseph Schlessinger
- Gerard Manning
Related topics
Seminal works
- krebs-fischer-1955
- manning-2002
- lemmon-2010
Frequently asked questions
- Why is phosphorylation such a common control mechanism?
- It is fast, reversible, and uses ATP that the cell already maintains; adding or removing a charged phosphate can rapidly switch a protein's activity on or off, making it an efficient and tunable regulatory device.
- What is the difference between serine/threonine and tyrosine kinases?
- They differ in the residue they phosphorylate: serine/threonine kinases add phosphate to serine or threonine residues, while tyrosine kinases act on tyrosine residues; both transfer phosphate from ATP, but they recognise different substrates and pathways.