The angiotensin II type 1 receptor C-terminal Lys residues interact with tubulin and modulate receptor export

Xiaoping Zhang1, Hong Wang, Matthew T Duvernay

  • 1Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.

Plos One
|March 2, 2013
PubMed

Insights

Angiotensin II type 1 receptor (AT1R) transport relies on tubulin binding. Specific lysine residues in AT1R

Area of Science:

  • Molecular biology
  • Cellular transport mechanisms
  • Receptor trafficking

Background:

  • Angiotensin II type 1 receptor (AT1R) mediates angiotensin II's physiological and pathological roles.
  • The intracellular transport pathway of AT1R from the endoplasmic reticulum (ER) to the cell surface is not well understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing the cell surface transport of newly synthesized AT1R.
  • To identify specific interactions involved in AT1R trafficking.

Main Methods:

  • Investigated the interaction between AT1R's C-terminus (CT) and tubulin using biochemical binding assays.
  • Mapped the binding domains on both AT1R and tubulin.
  • Utilized site-directed mutagenesis to disrupt AT1R-tubulin binding.
  • Assessed cell surface expression of AT1R and AT1R-mediated signaling (ERK1/2 activation) in wild-type and mutant receptors.

Main Results:

  • Demonstrated a direct and strong binding interaction between the AT1R C-terminus and tubulin.
  • Identified two specific lysine residues (Lys310 and Lys311) in the AT1R CT juxtamembrane region and the acidic CT of tubulin as key binding sites, suggesting ionic interactions.
  • Disruption of tubulin binding via mutation significantly inhibited AT1R cell surface expression and caused AT1R to accumulate in the ER.
  • Attenuated AT1R-mediated ERK1/2 activation signaling.

Conclusions:

  • Specific lysine residues in the AT1R C-terminus are critical for its interaction with tubulin.
  • This AT1R-tubulin interaction regulates AT1R processing and transport from the ER to the cell surface.
  • The microtubule network plays a significant role in AT1R cell surface delivery.

Related Concept Videos

Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Antihypertensive Drugs: Angiotensin II Receptor Blockers01:30

Antihypertensive Drugs: Angiotensin II Receptor Blockers

In the renin-angiotensin-aldosterone system, a hormone called angiotensin II plays a crucial role. It binds to the AT1 receptors in vascular smooth muscles coupled with Gq proteins. The activation of these receptors activates an enzyme called phospholipase C, which releases two molecules: inositol trisphosphate and diacylglycerol. These molecules cause a chain reaction that leads to the phosphorylation of myosin light chains and promotes interaction between actin and myosin, leading to smooth...
Enzyme-linked Receptors01:00

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
Enzyme-linked Receptors01:00

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
Tail-anchoring of Proteins in the ER Membrane01:45

Tail-anchoring of Proteins in the ER Membrane

Tail-anchored, or TA, proteins are estimated to make up to 3-5% of membrane proteins found in the eukaryotic cell. Such proteins have a single transmembrane domain located approximately 30 amino acid residues upstream from the C-terminal end. As a result, the signal recognition particle (SRP) cannot guide a TA protein to the ER membrane for cotranslational insertion. Hence, they are integrated into the ER membrane post-translationally using their C-terminal end as the anchor. TA proteins...
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...