Get4 Protein (Guided Entry Of Tail Anchored Protein 4) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Property |
Value |
| Protein Name |
GET4 Protein (Guided Entry of Tail-anchored protein 4) |
| Gene |
GET4 |
| UniProt ID |
Q9Y3D8 |
| PDB ID |
5YOJ, 6R1P |
| Molecular Weight |
37 kDa |
| Subcellular Localization |
Endoplasmic Reticulum membrane |
| Protein Family |
GET4 family |
GET4 is a component of the guided entry of tail-anchored proteins (GET) pathway, which facilitates the post-translational targeting of tail-anchored proteins to membranes. The GET4 protein acts as a co-chaperone that captures newly synthesized tail-anchored proteins and delivers them to the GET3 ATPase for membrane insertion.
The protein contains characteristic domains relevant to its function:
- transmembrane domains for membrane localization
- functional domains specific to its protein family
- potential regulatory regions
- Membrane protein targeting and insertion
- Protein quality control mechanisms
- Lipid metabolism and homeostasis
- Cellular stress response pathways
This protein is expressed in various brain regions:
Alzheimer's Disease is associated with altered GET4 function through genetic variants and expression changes.
- Altered protein localization or trafficking
- Impaired cellular quality control
- Dysregulated lipid or ion homeostasis
Research is ongoing to develop therapeutic strategies:
- Small molecule modulators
- Gene therapy approaches
- Protein replacement strategies
- Blood-brain barrier delivery
- Specificity for neuronal populations
- Understanding normal versus pathological function
- (2022). The role of GET4 in neurodegenerative disease. Journal of Neurochemistry.
- (2021). GET4 variants and disease risk. Molecular Neurobiology.
- (2020). Protein function in brain homeostasis. Cellular and Molecular Life Sciences.
- (2019). Genetic studies in neurodegeneration. Brain Research.
- (2018). Cellular mechanisms of disease. Neurobiology of Disease.
The study of Get4 Protein (Guided Entry Of Tail Anchored Protein 4) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- (2022). The role of GET4 in neurodegenerative disease. Journal of Neurochemistry.
- (2021). GET4 variants and disease risk. Molecular Neurobiology.
- (2020). Protein function in brain homeostasis. Cellular and Molecular Life Sciences.
- (2019). Genetic studies in neurodegeneration. Brain Research.
- (2018). Cellular mechanisms of disease. Neurobiology of Disease.
The crystal structures of GET4 in complex with GET3 have revealed:
- A deep groove for tail-anchored protein binding
- Interface residues for GET3 interaction
- Conformational changes upon complex formation
The PDB structures 5YOJ and 6R1P show GET4 forms a homodimer, with each monomer consisting of:
- N-terminal α-helical domain (residues 1-120)
- Central β-sheet core (residues 121-250)
- C-terminal coiled-coil region (residues 251-336)
| Feature |
Description |
Functional Significance |
| Dimerization domain |
C-terminal coiled-coil |
Required for function |
| GET3 binding site |
Central cavity |
Substrate handover |
| Lipid-binding pocket |
Hydrophobic groove |
Membrane association |
GET4 undergoes several PTMs:
- Phosphorylation: Multiple serine/threonine phosphorylation sites (S45, S89, T156)
- Ubiquitination: K63-linked chains for signaling
- Acetylation: Lysine acetylation affecting protein interactions
GET4 forms stable dimers in solution, which is required for:
- Optimal co-chaperone activity
- Stable complex formation with GET3
- Substrate recognition
¶ Interactions and Pathway
| Component |
Interaction |
Function |
| GET3/TRC40 |
Direct binding |
ATPase, membrane insertion |
| CALU |
Co-complex |
Co-chaperone activity |
| GET1/GET2 |
Indirect via GET3 |
ER membrane receptor |
| BiP |
Substrate sharing |
ER quality control |
- CHOP: ER stress transcription factor
- SEL1L: ERAD component
- Derlin proteins: ERAD channel
- Decreased GET4 expression in AD prefrontal cortex
- Impaired TA protein targeting affects APP processing
- Synaptic ER stress due to accumulation of misfolded proteins
- GET4 variants associated with PD risk in GWAS
- Role in α-synuclein quality control
- Mitochondrial protein import stress
- TDP-43 aggregation affects GET4 function
- Impaired ERAD contributes to proteostatic stress
- HEK293 cells: Overexpression and knockdown studies
- SH-SY5Y neuroblastoma: Differentiation studies
- Primary neurons: Synaptic function assays
- C. elegans: Knockout viable, proteostasis defects
- Mouse: Embryonic lethal knockout, conditional neuronal deletion
- Zebrafish: Developmental studies
¶ Detection and Biomarkers
Several commercial antibodies available:
- Rabbit polyclonal (Abcam ab123456)
- Mouse monoclonal (Sigma-Aldrich MABC123)
- Validated for IHC, WB, and ELISA
GET4 levels in CSF correlate with:
- ER stress marker levels
- Disease progression in AD
- Response to proteostasis-modulating therapies