Biochemistry Online: An Approach Based on Chemical Logic

CHAPTER 9 - SIGNAL TRANSDUCTION

C: SIGNALING PROTEINS

BIOCHEMISTRY - DR. JAKUBOWSKI

04/16/16

Learning Goals/Objectives for Chapter 9C:
After class and this reading, students will be able to

define kinases and phosphatases and their role in signal transduction
define primary and secondary messengers and give specific examples of each
describe the role of G proteins in coupling ligand induced conformational changes in the bound receptor to activation of specific effector proteins such as adenylate cyclase and phospholipase
differentiate between kinases activated by second messengers and those activated by primary messengers (ligand-gated receptor Tyr kinases)
describe the structural characteristics of G protein coupled serpentine receptors and ligand gated receptor tyrosine kinases
draw a diagram showing the general features of kinases mediated signal transduction pathways that lead to activation of gene expression
differentiate between neuron responses mediated by neurotransmitters on binding gated receptor/ion channels compares to G-protein coupled receptors

Estonian Translation √ by Anna Galovich

C1. Signaling Kinases

Lastly, we will consider general mechanisms for signal transduction across membranes of any cell that must respond to its environment. Typically the agent that signals a cell to respond is a molecule (or in the case of light sensation a photon) which binds either to a cell surface receptor or to a cytoplasmic receptor if the signaling agent is hydrophobic. In almost all cases, such signaling activates protein kinases in the cell. Kinases are a class of enzymes which use ATP to phosphorylate molecules within the cell.

The names given to kinases shows the substrate which is phosphorylated by the enzyme. For example:

Hexokinase - an enzyme that uses ATP to phosphorylate hexoses.
Protein kinase - enzymes that use ATP to phosphorylate proteins within the cell. (Note: Hexokinase is a protein, but is not a protein kinase).
Phosphorylase Kinase: an enzyme that use ATP to phosphorylate the protein phosphorylase within the cell

If a protein is phosphorylated by a kinase, the phosphate group must eventually be removed by a phosphatase through hydrolysis. If it wasn't, the phosphorylated protein would be in a constant state of either being activated or inhibited. Kinases and phosphatases regulate all aspects of cellular function. Some people estimate that 1-2% of the entire genome may encode kinases and phosphatases. There appears to be about 518 different protein kinases in humans.

Kinases can be classified in many ways. One is substrate specificity: Eukaryotes have different kinases that phosphorylate Ser/Thr or Tyr. Prokaryotes also have His and Asp kinases but these are unrelated structurally to the eukaryotic kinases. There are 11 structurally different families of eukaryotic kinases, which all fold to a similar active site with an activation loop and catalytic loop between which substrates bind. Simple, single cell eukaryotic cells (like yeast) have predominantly cytoplasmic Ser/Thr kinases, while more complex eukaryotic cells (like human) have many Tyr kinases. These include the membrane-receptor Tyr kinases and the cytoplasmic Src kinases.

Manning et al. have analyzed the entire human genome (DNA and transcripts) and have identified 518 different protein kinases, which cluster into 7 main families as shown in the table below. Family membership was determined by sequence comparisons of catalytic domains. They have named the entire repertoire of kinases in the genome the kinome. Alterations in 218 of these appear to be associated with human diseases.

The Kinome

Name	Description
AGC	Contain PKA, PKG, and PKC families
CAMK	Ca2+/CAM-dependent PK
CKI	Casein kinase 1
CMGC	Contain CDK, MAPK,GSK3, CLK families
STE	homologs of yeast sterile 7, 11, 20 kinases; MAP Kinase
PTK	Protein tyrosine kinase
PTKL	Protein tyrosine kinase-like
RGC	Receptor guanylate kinase

In this chapter we will review the activation by extracellular signals of the kinases in red in the table above. These kinases phosphorylate other proteins within the cell and through associated conformational and charge changes, the phosphorylated proteins are either activated or inhibited in the expression of biological activity.

Figure: five major protein kinases

Sig Trans

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