ATG17 (also known as RB1CC1 or FIP200) encodes a critical scaffold protein in the autophagy initiation machinery. Formerly named ATG17 (Autophagy Related 17), the gene was renamed RB1CC1 (RB1 Inducible Coiled-Coil 1) due to its discovery as a RB1 tumor suppressor-interacting protein, while FIP200 (Focal Adhesion Kinase Family Interacting Protein of 200 kDa) remains a widely used alternate name. This protein forms the backbone of the ULK1 complex that nucleates autophagosome formation, making it essential for cellular homeostasis and survival[1].
| RB1CC1/FIP200/ATG17 | |
|---|---|
| Gene Symbol | ATG17 (RB1CC1) |
| Full Name | RB1 Inducible Coiled-Coil 1 |
| Chromosome | 8q11.23 |
| NCBI Gene ID | [9881](https://www.ncbi.nlm.nih.gov/gene/9881) |
| OMIM | 604791 |
| Ensembl ID | ENSG00000055118 |
| UniProt ID | [Q8TF72](https://www.uniprot.org/uniprot/Q8TF72) |
| Protein Class | Scaffold Protein / Autophagy Initiation |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), ALS, FTD, Cancer |
The ATG17 gene spans approximately 40 kb on chromosome 8q11.23 and consists of 46 exons encoding a 1,524 amino acid protein with a molecular weight of approximately 200 kDa. The gene exhibits broad tissue expression with particularly high levels in the brain, heart, and skeletal muscle.
The RB1CC1/FIP200 protein contains several critical functional domains[2]:
| Domain | Position | Function |
|---|---|---|
| N-terminal coiled-coil domain | 1-400 | Homodimerization, ULK1/2 binding |
| FIP200 interaction domain | 400-800 | Self-association, complex formation |
| ATG101 binding region | 800-1100 | ATG101 recruitment |
| C-terminal focal adhesion targeting (FAT) domain | 1400-1524 | Subcellular localization |
| LC3-interacting region (LIR) | Multiple | Selective autophagy receptor binding |
The protein functions as a homodimer through its N-terminal coiled-coil domains, creating a elongated dimeric structure that serves as a platform for complex assembly. The multiple LIR motifs enable interaction with various autophagy receptors during selective autophagy processes.
While yeast Atg17 is a smaller 37 kDa protein, mammalian RB1CC1/FIP200 represents a functionally conserved ortholog with additional domains acquired during evolution. The core scaffolding function is conserved, but mammalian RB1CC1 has acquired additional regulatory functions through protein-protein interactions[3].
ATG17/RB1CC1 forms the central scaffold of the ULK1 complex, which consists of four core components[4][5]:
The complex has a stoichiometry of 1:1:2:1 for ULK1:ATG13:ATG17:ATG101, with ATG17 forming a dimer that provides two binding sites for ULK1-ATG13 dimers.
The ULK1 complex responds to cellular nutrient status through two primary regulatory pathways[6]:
mTORC1 Inhibition Pathway:
AMPK Activation Pathway:
Once activated, the ULK1 complex translocates to the phagophore assembly site (PAS), where ATG17 plays a critical scaffolding role[7]:
ATG17 coordinates with the ATG12-ATG5-ATG16L1 conjugation system to facilitate LC3 lipidation:
The complex remains associated with the expanding phagophore until closure:
Autophagy is profoundly impaired in Alzheimer's disease, and ATG17 dysfunction contributes to disease pathogenesis through multiple mechanisms[7:1][8]:
Amyloid-β Clearance:
Tau Pathology:
Neuronal Vulnerability:
ATG17 is critical for mitophagy—the selective autophagy of damaged mitochondria[9]:
PINK1-PARKIN Pathway:
Dopaminergic Neuron Survival:
Therapeutic Implications:
Mutations in ATG17/RB1CC1 have been linked to ALS and FTD[10]:
FIP200 Mutations:
Therapeutic Targeting:
ATG17 interacts with multiple proteins to coordinate autophagy initiation[11]:
| Protein | Interaction Type | Functional Role |
|---|---|---|
| ULK1 | Direct binding | Kinase activation, complex assembly |
| ULK2 | Direct binding | Redundant kinase function |
| ATG13 | Direct binding | Regulatory subunit |
| ATG101 | Direct binding | Complex stabilization |
| VPS34 | Indirect via recruitment | PI3K recruitment |
| BECN1 | Indirect via recruitment | PI3K complex component |
| RB1 | Direct binding | Tumor suppressor function |
| FAK | Direct binding | Cell adhesion signaling |
| p53 | Transcriptional regulation | Tumor suppression |
ATG17 is widely expressed in the central nervous system:
| Brain Region | Expression Level | Significance |
|---|---|---|
| Cerebral Cortex | High | High neuronal density, elevated autophagy demand |
| Hippocampus | High | Memory formation, CA1 particularly vulnerable |
| Basal Ganglia | High | Dopaminergic neuron maintenance |
| Cerebellum | High | Purkinje cell function |
| Brainstem | Moderate | Vital function maintenance |
| White Matter | Lower | Lower metabolic activity |
ATG17 expression and activity are regulated at multiple levels:
Several strategies to enhance ATG17 function are under development[12]:
ULK1 Kinase Activators:
mTOR Inhibitors:
Autophagy Enhancers:
Autophagy and neurodegenerative disease. Cell. 2022. ↩︎
Cellular stress response pathways and autophagy. J Mol Biol. 2021. ↩︎
Atg17 in yeast autophagy. Autophagy. 2010. ↩︎
ULK1 complex - autophagy initiation. Mol Biol Cell. 2012. ↩︎
ULK1 complex composition and function. J Cell Biol. 2013. ↩︎
ULK1 complex regulation by mTOR and AMPK. Mol Cells. 2021. ↩︎
The involvement of autophagy in Alzheimer's disease. Nat Rev Neurol. 2020. ↩︎ ↩︎
Autophagy modulation as therapeutic strategy in AD. Brain. 2022. ↩︎
ATG17 in mitophagy and Parkinson's disease. J Neurosci. 2022. ↩︎
FIP200 mutations in ALS/FTD. Nat Neurosci. 2020. ↩︎
RB1CC1 in cancer and autophagy. Autophagy. 2020. ↩︎
Autophagy and protein clearance in neurodegeneration. Trends Neurosci. 2016. ↩︎