Week 3 - L3 Study Notes on Enzyme Coupled Receptors and Receptor Tyrosine Kinases

Enzyme Coupled Receptors

Overview of Enzyme Coupled Receptors

• Definition: A class of receptors classified as enzymes that couple receptor activity with enzymatic functions.

• Broad Classification: Six subfamilies identified in enzyme-coupled receptors.

Subfamilies of Enzyme Coupled Receptors

1. Receptor Tyrosine Kinases (RTKs)

   • Most common family.

   • Function: Phosphorylate specific tyrosine residues on target proteins.

   • Importance: Focus of this discussion.

2. Tyrosine Kinase Associated Receptors

   • Do not possess their own kinase activity.

   • Function: Associate closely with tyrosine kinase molecules to perform phosphorylation.

   • Brief coverage towards the end of the video.

3. Receptor Serine/Threonine Kinases

   • Function: Phosphorylate serine or threonine residues (similar to tyrosine kinases).

4. Histidine Kinase Associated Receptors

   • Do not have intrinsic enzymatic capacity.

5. Receptor Tyrosine Phosphatases

   • Function: Remove phosphate groups from tyrosine residues (opposite of kinases).

6. Receptor Guanylyl Cyclases

   • Function: Catalyze the production of cyclic GMP.

Receptor Tyrosine Kinases (RTKs)

• General Function: Responsible for phosphorylating tyrosine residues.

• Key Examples:

  • Insulin Receptor: Critical for glucose metabolism.

  • Insulin-like Growth Factor Receptor (IGF-1): Similar functions related to growth.

  • Growth Factor Receptors:

    • EGF Receptor (Epidermal Growth Factor Receptor): Focused research topic for the presenter.

    • PDGF Receptor (Platelet-derived Growth Factor Receptor).

    • VEGF Receptor (Vascular Endothelial Growth Factor Receptor).

• Common Structural Features:

  • Extracellular domain interacts with ligands.

  • Intracellular tyrosine kinase domain: responsible for phosphorylating downstream targets.

  • Presence of a typical or split tyrosine kinase domain in various receptors.

Signaling Mechanism of RTKs

• Inactive State:

  • May exist as monomers (single protein) or dimers (two protein units bound together).

• Activation:

  • Ligand binding induces dimerization, leading to a process called transautophosphorylation, where one receptor phosphorylates the other.

  • Conformational changes can facilitate this phosphorylation.

• Phosphorylation Cascade:

  • Initial phosphorylation opens up additional binding sites for downstream signaling molecules.

Key Signaling Molecules and Domains

• SH2 and SH3 Domains: Recognize and bind specific residues.

  • SH2 Domain: Binds phosphorylated tyrosines on receptors.

  • SH3 Domain: Binds proline-rich sequences in other proteins.

• PTB Domain: Similar function to SH2; binds phosphorylated tyrosines but differs in structure.

• PH Domains: Recognize hyperphosphorylated inositides.

Classes of Proteins in Signaling

• Adapter Proteins: Act as a link or bridge in signaling networks, similar to electrical adapters connecting plugs.

  • Can connect receptors with downstream proteins lacking SH2 domains.

• Scaffold Proteins: Link multiple proteins within signaling pathways, promoting rapid activation of downstream targets.

Example of Insulin Receptor Mechanism

• Components involved:

  • IRS-1 (Insulin Receptor Substrate 1): Acts as a docking protein and forms a crucial part of signaling after receptor activation.

  • GRAB2: An adapter protein that interacts with IRS-1 after its activation.

  • Scaffold Protein: Links multiple proteins, allowing coordinated signaling.

• Sequence of Events:

  1. Insulin receptor gets activated upon ligand binding (dimerization).

  2. IRS-1 binds, gets phosphorylated, and provides docking sites for GRAB2.

  3. Additional downstream proteins activated resulting in a multiply activated signaling network.

Platelet-Derived Growth Factor Receptor Example

• Contains multiple phosphorylatable tyrosine residues, which serve as docking sites for various signaling molecules targeting specific residues.

• Has a split tyrosine kinase domain that enables multiple phosphorylation events.

Molecular Switches in Signaling

GTPase Mechanism

• Definition: Enzymes activated by GTP; involve GDP to GTP exchange for activation.

• Guanine Nucleotide Exchange Factor (GEF): Promotes GDP-GTP exchange, activating GTPase.

• GTPase Activating Protein (GAP):

  • Accelerates GTPase activity but is named misleadingly since it promotes hydrolysis back to GDP (deactivating it).

• RAS Family Proteins: Important GTPase proteins associated with RTK signaling; mutations can lead to cancer through overactivation of growth pathways.

Conclusion and Analysis

• Acknowledges complexity in RTK signaling, and prospects for further exploration of specific pathways and mechanisms in the next video.