Introduction to Kinases
Contents
Introduction to Protein Kinases
Protein Kinases are enzymes that modify the function of other proteins by attaching phosphate groups to them. They are key controllers of most biochemical pathways and important in health and disease.
The kinase reaction
Protein Kinases bind substrate proteins and ATP and transfer a phosphate group from ATP to amino acids with free hydroxyl gropus (serine, threonine or tyrosine). Most kinases act on serine or threonine, while some are specific to tyrosine, and some act on all three. The phosphate group (PO4-) is negatively charged and changes the substrate protein in different ways – altering activity (including other kinases), the location of the protein, it’s turnover or it’s interactions with other proteins. These changes can be reversed by a separate class of enzymes called phosphatases, that remove the phosphate groups (graphic of kinase/phosphatase reaction).
Enzymology
Basic Reaction
Substrate AAs and oddball kinases
Show structures of ser, thr and tyr His-Asp and other possible kinases (and their rarity in human biology).
Special role of phosphotyrosine
Tyrosine phosphoryation has been of particular interest to many biologists, due to its biological roles. Even though only x% of cellular protein is tyrosine phosphorylated (compared with y% on Ser, z% on thr), these sites have strong biological functions, particularly in terms of communication between cells. Most tyrosine phosphorylation is carried out by a distinct group of ePK kinases, called TK (tyrosine kinase), though several ser/thr-looking kinases also have tyrosine kinase abilities (so-called dual-specificity kinases). Most TKs are either receptor tyrosine kinases (RTKs) whose extracellular region senses extracellular signals, or are receptor-associated kinases (is this a term?) that are located near the surface of the cell and interact with RTKs.
Range of Biochemical Substrates
What does phosphorylation do? – activate, relocate etc.
Biological Functions
All the things that Kinases influence Cell Cycle Growth Response Pathways DNA damage Translational Control
Kinases and Disease
As key regulators, protein kinases have strong effects when misregulated. A large number of kinases are known to be mutated or misregulated in various diseases, while on the flip side, inhibition of kinases by drugs is a major area of research for disease therapy.
A list of kinases implicated in disease, and some drug information is available at http://www.cellsignal.com/reference/kinase_disease.asp
Evolution, genomics
Most human protein kinases share a common structural domain, the ePK (eukaryotic protein kinase) domain. Kinases with this domain are almost exclusively eukaryotic, and consitute one of the largest eukaryotic gene families, representing 1-4% of all genes in sequenced genomes. Comparison of the kinomes of several divergent genomes indicates that the most primitive eukaryote had about 35 distinct kinase functions. Humans have 518 protein kinase genes
Classification
Acessory subunits and pathway data?
Structure and mechanism (enzymology revisited)
- in-depth analysis of the 3D structure, including secondary structure elements, key residues, faces for regulation, autophosphorylation, differences between groups etc.
Enz. mechanism
Key residues and key group-specific residues
Activation and control mechanisms
– autophos and various regulatory subunits
