Enzyme coupled receptors.pptx

Enzyme coupled receptors

1. SIGNALING THROUGH Enzyme – coupled receptors, rtkS P:3 u:2 VEDANTI S. GHARAT ROLL NO. – 09 M.Sc. Part-1

2. Enzyme - coupled receptors They are the second major type of cell- surface receptor. Are a group of multi-subunit transmembrane proteins that contain either intrinsic enzyme activity on their intracellular domain or associate directly with an intracellular enzyme. Like GPCRs, enzyme-linked receptors are transmembrane proteins with their ligand-binding domain on the outer surface of the plasma membrane. G-protein linked receptor protein has 7 transmembrane segments, each subunit of a catalytic receptor usually has only one. Are the receptors for many growth factors, cytokines and hormones and have a major role in regulation of cell growth, proliferation and differentiation.

3. Classes of enzyme- linked receptors There are six known classes of enzyme-linked receptors: (1) Receptor guanylyl cyclases (2) Receptor tyrosine kinases (3) Tyrosine-kinase-associated receptors (4) Receptor tyrosine phosphatases (5) Receptor serine/threonine kinases (6) Histidine-kinase-associated receptors

4. RECEPTOR TYROSINE KINASES [RTKs] Receptor tyrosine kinases (RTKs) are  enzyme-linked receptors localized at the plasma membrane containing an extracellular ligand-binding domain, a transmembrane domain, and an intracellular protein–tyrosine kinase domain. They phosphorylate specific tyrosine residues on a small set of signaling proteins. The human genome encodes nearly 60 RTKs. They are activated directly by extracellular growth factors and differentiation factors.

5. Members of this family include receptors for the epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1).

6. Steps in activation of rtks ( a) Ligand-mediated dimerization . In the nonactivated state , the receptors are present in the membrane as monomers. Binding of a bivalent ligand leads directly to dimerization of the receptor and activation of its kinase activity, causing it to add phosphate groups to the cytoplasmic domain of the other receptor subunit. The newly formed phosphotyrosine residues of the receptor serve as binding sites for target proteins containing either SH2 or PTB domains. The target proteins become activated as a result of their interaction with the receptor. ( b) Receptor-mediated dimerization . The sequence of events are similar to those in part a, except that the ligand is monovalent and, consequently, a separate ligand molecule binds to each of the inactive monomers . Binding of each ligand induces a conformational change in the receptor that creates a dimerization interface (red arrows). The ligand-bound monomers interact through this interface to become an active dimer.

7. How does the binding of an extracellular ligand activate the kinase domain on the other side of the plasma membrane? Ligand binding causes the receptor to assemble into dimers, which enables the two cytoplasmic domains to cross-phosphorylate each other on multiple tyrosine residues. This cross- phosphorylation is referred to as autophosphorylation because it occurs within the receptor dimer . In the case of PDGF receptors, the ligand is a dimer that cross-links two receptors together. EGF , is a monomer that is thought to induce a conformational change in the extracellular domain of its receptors to induce receptor dimerization . It is thought that receptor dimerization is a general mechanism for activating enzyme-linked receptors with a single transmembrane domain.

8. Autophosphorylation sites on RTKs can carry out two different functions: they can regulate the receptor’s kinase activity or serve as binding sites for cytoplasmic signaling molecules . Autophosphorylation is thought to serve as a switch to trigger the transient assembly of an intracellular signaling complex, which serves to relay the signal into the cell interior . Different receptor tyrosine kinases bind different combinations of these signaling proteins and therefore activate different responses . The activated receptor and its bound signaling proteins form a signaling complex that can then broadcast signals along multiple signaling pathways.

9. Inhibition of signaling Receptor dimerization can be exploited experimentally to inactivate specific receptors. The strategy involves transfecting cells with DNA that encodes a mutant form of a receptor tyrosine kinase that dimerizes normally but has an inactive kinase domain . When coexpressed at a high level with normal receptors, the mutant receptor acts in a dominant-negative way, disabling the normal receptors by forming an inactive dimer with them . The mutant receptor with an inactivated kinase domain can dimerize normally, but it cannot cross- phosphorylate a normal receptor in a dimer. For this reason, the mutant receptors, if present in excess, will block signaling by the normal receptors- a process called dominant-negative inhibition.

10. bibliography Karp- cell and molecular biology book Molecular biology of the cell by Albert's. Images were taken by Google. THANKYOU