Receptors

Receptor and its types with Rtks

1. Receptors and its Types M.Zafar Mphil Microbiology 1 st semester AWKUM

2. Contents Definition Types of receptors Mechanism of Actions Tyrosine Kinase RTKS Disorders Associated with Receptors

3. What is a Receptor ?? Receptor is a Macromolecule protein which binds to a specific molecule. The molecule Which binds it Called the  ligand .  A ligand may be any molecule, from inorganic minerals to organism-created hormones, proteins and neurotransmitters. The ligand binds to the ligand -binding site on the receptor protein. after this binding o the receptor undergoes a  conformational change.

4. There are many types of receptors, but they all have one thing same : they occures in closely matched pairs, with a receptor can bind to just one (or a few) specific ligands , and a ligand binding to just one (or a few) target receptors. Binding of a ligand to a target receptor results in changing its shape or function allowing it to transmit a signal or directly produce a change inside of the cell.

5. How Receptor works

6. How Receptor works

7. Receptors come in different types, they are classify into two groups: 1. intracellular receptors: which are present inside in cell ( cytoplasm or nucleus) 2. cell surface receptors: which are present in the plasma membrane. Types of Receptors

8. Intracellular receptors Intracellular receptors  are those receptor proteins present inside of the cell, eg cytoplasm or nucleus. In many cases, the ligands of intracellular receptors are small in size, hydrophobic molecules, so they can cross the plasma membrane to reach their receptors. eg the primary receptors for hydrophobic steroid hormones, such as the sex hormones estradiol (E2) (an estrogen) and testosterone, are intracellular.

9. Intracellular receptors After the entry of a hormone to a cell it binds to its target receptor, it causes the receptor to change shape, allowing the receptor-hormone complex to enter the nucleus and regulate gene activity.

10. Cell-surface receptors Cell-surface receptors  are those Protein receptors to which ligands binds on the outside surface of the cell. In this type of action, the ligand molecule does not needs to cross the plasma membrane of the cell. many large size different kinds of molecules may act as ligands .

11. Structure of CSR A cell-surface receptor has 03 different  domains or protein regions: (1) extracellular ligand -binding domain. (2) Hydrophobic domain extending through the membrane, (3) Intracellular domain, which transmits a signal.

12. Ligand -gated ion channels Ligand-gated ion channels  are ion channels, binding of a ligand to its receptor results in opening of the chanel . this kind of cell-surface receptor consist of a membrane-spanning region with a hydrophilic channel in the mid of cell membrane. The channel facilitate ions to cross the membrane without having any interaction with the hydrophobic core of the Phospholipids bilayer. 

13. Mechanism of Action When the ligand binds to the outer part of the channel, the protein’s structure changes in such a way that ions of a specific type, such Cl − can pass via chanel . In other cases, the opposite action is true: the channel is usually open, and binding of a ligand molecule causes it to close. Levels of ion Change inside the cell which leads to change the activity of other molecules. For example : Nicotinic acetylcholine (Ach) receptor

14. Ligand -gated ion channels

15. G protein-coupled receptors G protein-coupled receptors  ( GPCRs ) are a wide group of cell surface receptors that resemble a common structure and principle of signaling. The members of the GPCR group all have seven different protein segments that pass through membrane, and they transmit signals inside the cell through a type of protein is known as a G protein 

16. G protein-coupled receptors A GPCR waits inside the cell membrane in an inactive state. When the ligand of G protein-coupled receptor is absent.

17. What is a G proteins ? G proteins occures in many types, they all bind the to nucleotide guanosine triphosphate (GTP), which they can break down (hydrolyze) to form guanosine Diphosphate (GDP). A G protein stick to GTP is active, or “on,” and a G protein that’s attached to GDP is inactive, or “off.” The G proteins that joined to GPCRs are a type made up of three subunits, known as  heterotrimeric G proteins .

18. Mechanism of Action After binding the Ligand , however, the picture change : the GPCR is activated and causes the G protein to switch GDP for GTP. The now-active G protein separates into two parts (one called the alpha subunit, the other part composed of the Beta and gamma subunits), which are freed from the GPCR. The subunits can interact with other proteins, triggering a signaling pathway that leads to a activity.

19. Example of GPCR Beta-adrenergic receptors, which bind epinephrine

20. Enzyme-linked receptors Enzyme-linked receptors  are cell-surface receptors with intracellular region that are connected with an enzyme. In other cases, the intracellular region of the receptor absolutely   is  an enzyme that can catalyze a reaction. Some enzyme-linked receptors consist an intracellular region that collaborate with an enzyme

21. ELR Classification There are five Major types of enzyme-linked receptors: Receptor Tyrosine Kinase (RTK): Contains intrinsic tyrosine kinase activity (EGFR& VEGFR) Receptor Serine/ Threonine Kinase Receptor Guanylyl Cyclases Tyrosine- Kinase Associated Receptors Receptor Tyrosine Phosphatases

22. Receptor tyrosine kinases  ( RTKs ) RTKs are a class of enzyme-linked receptors present in humans and many other species.  ( RTKs ) are the high-affinity cell surface receptors for many polypeptide  growth factors  cytokines Hormones Adhesion etc

23. RTKS There are 58 RTKs discovered to date, which are further subdivided into 20 subfamilies, all of them have a basic structure containing of an  extra cellular ligand -binding region linked to an  intra cellular protein kinase (Enzyme) core via a single-pass transmembrane region.

24. What is a Tyrosine Kinase ? A  tyrosine kinase  are enzymes which can transfer a phosphate group from ATP to a protein inside the cell. It functions as an "on" or "off" switch in many cellular activities. Tyrosine kinases  are a subclass of   Protein kinase. The phosphate group is connected to the amino acid tyrosine on the protein. Tyrosine kinases belongs to a subgroup of the major class of protein

25. What is a Tyrosine Kinase ? Phosphorylation of proteins by kinases is an Vital activity in communicating signals inside a cell (signal transduction) and monitor cellular mechanisms, such as cell division. Protein kinases can undergoes mutated, remains in the "on" position, and cause uncontrolled growth of the cell, which is a crucial step for the initiation of cancer.

26. Mechanism of Action In this example, signaling ligand first bind to the extracellular domains of two Adjacent RTKs. After binding receptors then come close, or dimerize . The receptors then join phosphates to tyrosines in each others' intracellular domains. The phosphorylated tyrosine can transmit the signal to other molecules inside the cell. ( As shown in image )

27. In other cases, the phosphorylated receptors work as a docking sites for other proteins that consist special types of binding regions. A number of proteins contain these domains, and when one of these proteins binds, it can starts a subsequent signaling cascade that leads to a cellular activity.

28. RTKs are important in many signaling processes in humans. they bind to  growth factors , signaling molecules that promote cell division and survival. Growth factors include platelet-derived growth factor (PDGF), which are essential for wound healing. Nerve growth factor (NGF), which is essential for neuron must be continually supplied to certain types of neurons to keep them physiologically functional . Due to their role in growth factor signaling, receptor tyrosine kinases are essential in the body, but their activity must be kept in balance: overactive growth factor receptors are concerned with some types of malignancies .

29. Disorders Associated with Receptors Disorders Associated with RTKS

30. Kinasopathies Developmental receptor tyrosine kinasopathies Somatic mutations in receptor tyrosine kinasopathies

31. DRTKs Mutations Germline mutations disrupting RTK signaling pathways have been identified as the cause of a number of congenital malformation syndromes; we refer to this collection of disorders as the ‘developmental receptor tyrosine kinasopathies ’ (DRTKs). To date, at least 35 DRTKs have been described in the Online Mendelian Inheritance in Man (OMIM) database, caused by mutations in 15 RTK genes

32. DRTKs Mutations Skeletal abnormalities are over-represented in DRTKs; mutations. Specific mutations in genes during embryogenesis cause abnormalities in Osteoblast Osteoclast chondrocyte Proliferation growth, differentiation and apoptosis resulting in abnormal bone morphogenesis. Other affected systems include the CNS a.nd endocrine systems

33. Hartsfield syndrome

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36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572000/