Related Experiment Video

Updated: Aug 18, 2026

The Cell-based L-Glutathione Protection Assays to Study Endocytosis and Recycling of Plasma Membrane Proteins
09:22

The Cell-based L-Glutathione Protection Assays to Study Endocytosis and Recycling of Plasma Membrane Proteins

Published on: December 13, 2013

GGA proteins mediate the recycling pathway of memapsin 2 (BACE)

Xiangyuan He1, Feng Li, Wan-Pin Chang

  • 1Protein Studies Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, USA.

The Journal of Biological Chemistry
|December 24, 2004
PubMed

Insights

Memapsin 2 (BACE) recycling to the cell surface involves Golgi-localized gamma-ear-containing ARF-binding (GGA) proteins. GGA proteins and phosphorylated ACDL in BACE are crucial for endosome-to-trans-Golgi transport.

Area of Science:

  • Molecular biology
  • Cell biology
  • Neuroscience

Background:

  • Memapsin 2 (BACE) cleaves beta-amyloid precursor protein (APP), initiating amyloid-beta production linked to Alzheimer's disease.
  • BACE and APP traffic from the cell surface to endosomes for cleavage.
  • The cytosolic domain of BACE contains an acid cluster-dileucine motif (ACDL) that binds Golgi-localized gamma-ear-containing ARF-binding (GGA) proteins.

Purpose of the Study:

  • To investigate the role of GGA proteins in the intracellular trafficking of Memapsin 2 (BACE).
  • To elucidate the mechanism of BACE recycling from endosomes to the trans-Golgi network.

Main Methods:

  • Colocalization studies of BACE, GGA proteins, and mannose-6-phosphate receptor chimeras in the trans-Golgi network and endosomes.
  • RNA interference to deplete cellular GGA proteins.
  • Site-directed mutagenesis of the BACE ACDL motif (Serine 498 phosphorylation).
  • Depletion of retromer subunit VPS26.

Main Results:

  • GGA proteins colocalize with BACE in the trans-Golgi network and endosomes.
  • Depletion of GGA proteins or disruption of BACE ACDL phosphorylation leads to BACE accumulation in early endosomes.
  • VPS26 depletion also alters BACE localization, indicating a role for the retromer pathway.

Conclusions:

  • GGA proteins, in conjunction with the phosphorylated ACDL motif of BACE, are essential for the endosome-to-trans-Golgi recycling pathway.
  • This pathway is critical for returning BACE to the cell surface.
  • Understanding BACE trafficking is vital for Alzheimer's disease research.

More Related Videos

Using an α-Bungarotoxin Binding Site Tag to Study GABA A Receptor Membrane Localization and Trafficking11:57

Using an α-Bungarotoxin Binding Site Tag to Study GABA A Receptor Membrane Localization and Trafficking

Published on: March 28, 2014

Analysis of Endocytic Uptake and Retrograde Transport to the Trans-Golgi Network Using Functionalized Nanobodies in Cultured Cells11:05

Analysis of Endocytic Uptake and Retrograde Transport to the Trans-Golgi Network Using Functionalized Nanobodies in Cultured Cells

Published on: February 21, 2019

Related Concept Videos

Recycling Endosomes and Transcytosis00:58

Recycling Endosomes and Transcytosis

The recycling endosome, also known as the endosomal recycling compartment (ERC), is a part of the slow-recycling process of the endocytic pathway. Molecules internalized through receptor-mediated endocytosis are either degraded in the lysosomes or are recycled to the plasma membrane through the fast- or slow-recycling route.
The recycling endosome is not a single organelle but an extensively tubulated network of recycling pathways. It functions in storing molecules or transporting them across...
ER Retrieval Pathway01:45

ER Retrieval Pathway

In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
Rab Cascades01:25

Rab Cascades

Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...