How do we get from a ligand binding to a heterotrimeric GTP-binding protein to the activation...

How do we get from a ligand binding to a heterotrimeric GTP-binding protein to the activation of PKA?

Expert Solution

GPCR (G-Protein Coupled Binding receptors) are a large family of transmembrane proteins. They consist of seven transmembrane alpha-helices with three extracellular and three intracellular loops. On the extracellular surface of this receptor binds the ligand, while on the intracellular surface is present the binding site for the GTP-activated protein (G-protein).

The structure of the G-protein consists of three subunits (alpha, beta and gamma). This G-protein binds GDP at the alpha subunit in the inactive state. However, when the ligand binds to the ligand-binding site at the receptor extracellular surface, activation of the receptor leads to the replacement of GDP by GTP at the alpha subunit. This alpha subunit-GTP complex then displaces itself from the beta and gamma subunits and brings about response effectuation by binding to the effector (ion channels/proteins/enzymes).

There are different types of G-proteins, which are divided based on their response to the effector molecule. Generally, these types differ only in their alpha-subunit.

G_s- activation of adenylyl cyclase, the opening of calcium channels

G_i- inhibition of adenylyl cyclase, the opening of potassium channels

G_q - the activation of phospholipase C (PL_C)

G_o- inhibition of calcium channels

There are different pathways through which the GPCR can perform its activity:

a. Adenylyl-cyclase: cAMP pathway

b. Phospholipase C: IP₃-DAG Pathway

c. Channel regulation

The activation of PK_A (Protein Kinase A) occurs in the first pathway, i.e., the Adenylyl-cyclase: cAMP pathway. This pathway uses G_s subunit of the G-protein. The activation/inhibition of the effector does not take place directly but involves certain second messengers which relay the information from the receptor to the effector molecule. The second messenger, in this case, is the PK_A molecule. After the ligand binds to the receptor, the receptor is activated which in turn activates the G-protein. The GDP bound to the alpha subunit is replaced by GTP, after which the alpha-GTP dissociates from the beta and gamma subunits. This activated Gs-alpha subunit binds to and activates adenylyl cyclase (AC). Adenylyl cyclase is responsible for catalyzing the conversion of ATP to cAMP (cyclic AMP). Intracellular accumulation of cAMP activates the enzyme PK_A. Thus, the activation of cAMP-dependent PK_A results in the phosphorylation of many proteins, ion channels, enzymes and transporters, thus altering their function. Thus, the GPCR brings about a response (activation/inhibition) by altering the activity of the effector molecule.

gladiator answered 1 year ago

how to increase a binding between a ligand ( etravirine) and a protein ( Human immunodeficiency...

how to increase a binding between a ligand ( etravirine) and a protein ( Human immunodeficiency virus type 1 HIV-1). disscusion should be based on thermodynamic theory

How do we get crystals of protein by various methods?

Upon binding of a ligand, G-protein-coupled receptors do which of the following? Select one: a. The...

Upon binding of a ligand, G-protein-coupled receptors do which of the following? Select one: a. The G-protein exchanges a GDP for a GTP, and the alpha subunit detaches from the beta/gamma complex b. They dimerize, autophosphorylate, and trigger a cascade in intracellular signal transduction/phosphorylation c. They migrate to the nucleus to activate/repress specific genes d. They get internalized and start producing cAMP e. They induce apoptosis

Which of the following statements about heterotrimeric G proteins is FALSE. Upon activation by a G-protein...

Which of the following statements about heterotrimeric G proteins is FALSE. Upon activation by a G-protein coupled receptor, the G-protein usually breaks into two complexes, each of which can activate target proteins. The α subunit is bound to GTP when the protein is in the inactive state The activated a subunit switches itself off by hydrolyzing its bound GTP G-proteins can activate membrane-bound enzymes and ion channels Once activated by a receptor, the α subunit can dissociate from the receptor

Ras is a GTP-binding protein that is often mutated in cancer cells. Normal cells are stimulated...

Ras is a GTP-binding protein that is often mutated in cancer cells. Normal cells are stimulated to divide by receiving a signal from a growth factor through a receptor tyrosine kinase. When the receptor tyrosine kinase binds the growth factor, Ras is stimulated to bind GTP. Ras in turn activates proteins that promote cell proliferation. A common mutation in cancerous cells causes Ras to behave as though it were bound to GTP all the time. Suppose that there is a...

Please provide detail explanation. Thank you. When a small GTP-binding protein (GBP) is in the "on"...

Please provide detail explanation. Thank you. When a small GTP-binding protein (GBP) is in the "on" (active) state (select any/all answers that apply): a) its Switch I and Switch II domains tilt toward one another b) GDP is bound within the nucleotide-binding pocket of the GBP c) the GBP is incapable of hydrolyzing its bound GTP d) the Switch II domain is phosphorylated on multiple tyrosine residues e) the GBP can physically interact with downstream effector molecules

What does binding of its ligand do to a receptor kinase?

Upon binding to its ligand the GPCR becomes activated and Question options: inactivates G protein by...

Upon binding to its ligand the GPCR becomes activated and Question options: inactivates G protein by changing its affinity for GDP and causes it to exchange it for GTP activates G protein by phosphorylating it activates G protein by changing its affinity for GDP and causes it to exchange it for GTP activates G protein by changing its affinity for GTP and causes it to exchange it for GDP

Etanercept is a TNF-α antagonist composed of the dimeric fusion protein of extracellular ligand-binding portion of...

Etanercept is a TNF-α antagonist composed of the dimeric fusion protein of extracellular ligand-binding portion of the soluble 75-kDa TNF-α receptor II and the fragment-crystallisable (Fc) portion of human immunoglobulin (IgG).” Based on this quote, what does etanercept compete with? Where does etanercept and its competitor bind?

Cell Biology Short Answer Question: Review the steps for ligand-induced activation of effector protein mediated by...

Cell Biology Short Answer Question: Review the steps for ligand-induced activation of effector protein mediated by trimeric G proteins. Suppose you have isolated a mutant Gα that has increased GTPase activity, what effect would this mutation have on the G protein and the effector protein?

Question