Enzyme-Linked Receptors

These are transmembrane receptors linked with intracellular enzymes; physiological receptors consisting of an extracellular ligand-binding domain and an intracellular effector domain (intrinsic enzymatic activity) which activates the signal transduction pathway that leads to amplification and propagation of signals within the cell to alter cellular process via secondary messenger or transducers.

 

fig: Enzyme-linked receptors.

The receptor molecules consist of single polypeptide chains with large, cysteine-rich extracellular domains, a short hydrophobic transmembrane domain (single α-helix), and an intracellular region containing one or more protein kinase domains.

Signal Transduction Pathway:

1. Ligand Binding

The inactive state of receptors is monomeric; when activated, these receptors undergo conformational changes resulting in increased cytosolic enzyme activity. This response lasts from minutes to an hour.

2. Conformational Change

When the ligand binds to two of its receptor subunits it induces dimerization of the receptor - cross phosphorylation of the kinase domains on multiple tyrosine residues. 

3. Auto- phosphorylation

Binding of ligand and conformational changes- their intrinsic tyrosine kinase activity causes auto-phosphorylation and phosphorylates other peptides or proteins that subsequently activate other important cellular signals.

4. Kinase Cascade

The activation of a protein kinase cascade; recruiting enzymes: phosphor-tyrosine-presenting proteins can attract adaptor molecules, which in turn attract other transducer and leads to their phosphorylation (transfer of phosphate).  “This cascade of activations results in a multiplication of the initial signal.”

5. Gene Transcription

The secondary messengers amplify and transduce the hormonal signal by activating the transcription factor responsible for the transcription. The transcripted mRNA gets translated into the ribosome and carries out the physiological response.

6. Intercellular signal termination and Desensitization of the receptors

• The phosphorylated substrate proteins are acted upon by kinases and their action are terminated, but not before the signal has been greatly amplified.
• Frequent activation (dimerization) of the receptor promotes receptor internalization and subsequent degradation in the lysosomes.

Types of Enzyme-Linked Receptors:

• Receptor Tyrosine Kinases

        The most abundant type of enzyme-linked receptor- intracellular region possesses tyrosine kinase activity and causes kinase cascade of the Ras/ Raf pathway (e.g. ligand-Insulin). 

• Serine / Threonine kinase Receptors

     Protein ligands activate receptors that have a serine/threonine kinase domain which phosphorylates a gene regulatory protein and brings about cellular changes.

• JAK-STAT  Binding Receptors

        These receptors have no intrinsic enzymatic activity; it follows the JAK-STAT pathway, Janus kinase (JAK) phosphorylates signal transducers and activators of transcription (STATs), which translocate to the nucleus and regulate transcription.

• Toll-like Receptors

      The Toll-like receptor domain lacks intrinsic enzymatic activity; it recruits the interleukin-associated kinases for transcriptional activation of inflammatory genes.

• TNF-α Receptors

         The mechanism of action of tumor necrosis factor (TNF-α) signaling starts by timerazitation of the receptors and leads to subsequent phosphorylation of the transcriptional factors.

• Natriuretic Peptide  Receptors

       Natriuretic Peptide Receptors are the signaling pathways that regulate the synthesis of cyclic GMP in cells: decrease blood pressure, to reduce cardiac hypertrophy and fibrosis.

Major/ key Signal Transduction Pathway

Clinical Significance

The Enzyme-Linked or Catalytic receptors are involved in cell survival (e.g. sugar uptake by insulin action), proliferation, immunity and it also plays an important role in cancer therapy by the mechanisms of apoptosis. Imatinib, Vemurafenib, Ruxolitinib are just some of the drugs which act by these receptors.

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