1. Signal Response and Amplification
Signal Transduction
Signal Recognition
Extracellular domain
Signal Transmission
Transmembrane domain
Signal Response and Amplification
Intracellular domain

2. Biosignaling (Signal Transduction)
A signaling molecule interacts with the extracellular side of a
cell surface receptor (a transmembrane protein).
The receptor undergoes a conformational change, is activated
and interacts with other intracellular components.
A second signal is produced or the activity of a specific cellular
protein is affected, further affecting downstream cellular events.
4. The receptor returns to the pre-stimulated conformation.

3. Features of Signal Transducing Systems

4. Six General Types of Signal Transducers

5. G Protein Receptor Activation

6. Activation of Adenylate Cyclase

7. G protein structure

8. Coordination of Mg2+ is necessary for GTP binding to G proteins

9. Structure of G-alpha

10. Active vs Inactive G-alpha
Figure 13.7

11. Active vs Inactive G-alpha

12. GTPase mechanism

13. Signal Transduction - Insulin
Signal Recognition
Extracellular domain
Signal Transmission
Transmembrane domain
Signal Response and Amplification
Intracellular domain
Tyrosine Kinase

14. Receptor Tyrosine Kinases

15. Receptor Tyrosine Kinases

16. Insulin
Signaling

17. Insulin is synthesized as an inactive prohormone

18. Insulin
Signaling

19. Extracellular side of insulin receptor
Transmembrane portion of insulin receptor
(structure not solved)
Intracellular side of
insulin receptor
(unphosphorylated and phosphorylated)

20. Insulin
Signaling

21. Insulin
Signaling

22. SH2 and SH3 domains in Grb2

23. SH2 domain

24. SH3 domain binds to a polyproline
Figure 13.28

25. SH3 domain peptide complex

26. Insulin
Signaling

27. G protein (Ras) structure

28. GTP bound to Ras
A Mg2+ is coordinated to the β and γ phosphates of GTP and links GTP to Ras. The Mg2+ is also coordinated to Ser and Thr side chain oxygens and two water molecules.
Ras is prenylated (geranylgeranyl), anchoring it to the membrane surface.

29. Insulin
Signaling

30. Raf and MEK
Raf and MEK are Protein Kinases that phosphorylate target proteins.
Raf (bound to Ras for activation) phosphorylates MEK on two serine residues.
MEK (activated when phosphorylated by Raf) phosphorylates ERK on a threonine and a tyrosine.

31. Insulin Signaling
In unstimulated cells, most Ras is in the inactive form with bound GDP; binding of insulin to the insulin receptor leads to formation of the active Ras·GTP.
Activated Ras binds to the N-terminal domain of Raf, a serine/threonine kinase.
Raf binds to and phosphorylates MEK on two serines, activating it.
MEK is a dual-specificity protein kinase that phosphorylates MAP kinase (ERK) on threonine and tyrosine residues separated by a single amino acid. Phosphorylation at both sites is necessary for activation of ERK.
ERK phosphorylates many different proteins, including nuclear transcription factors, that mediate cellular responses.

32. ERK Structure
Structures of ERK in its inactive, unphosphorylated form (a) and active, phosphorylated form (b)
Phosphorylation of ERK by MEK at tyrosine 185 (pY185) and threonine 183 (pT183) leads to a marked conformational change in the phosphorylation lip (red). This change promotes dimerization of ERK and binding of its substrates, ATP and certain proteins.
The dimeric form of ERK (but not the monomeric form) can be translocated to the nucleus where it regulates the activity of a number of nuclear localized transcription factors , increasing production of mRNAs that encode specific proteins.