Auxilin (encoded by the DNAJC6 gene, also known as DNAJC6 or AUXILIN) is a 97 kDa neuronal co-chaperone of the Hsp40/DnaJ family that plays a critical role in clathrin-mediated endocytosis (CME) by facilitating the ATP-dependent disassembly of clathrin coats from synaptic vesicles[1]. Synaptic vesicle recycling occurs at rates of up to several hundred cycles per second at central synapses, and auxilin is essential for this high-throughput recycling by ensuring rapid and efficient uncoating.
Auxilin is specifically expressed in neurons and neuroendocrine cells where CME is heavily used. Mutations in DNAJC6 cause autosomal recessive early-onset Parkinson's disease and have been linked to intellectual disability and epilepsy. Beyond PD, auxilin dysfunction contributes to the pathogenesis of Alzheimer's disease, ALS, and other neurodegenerative conditions through impaired endocytic trafficking of key proteins including APP, α-synuclein, and BDNF receptors[2].
The human DNAJC6 gene is located on chromosome 1p31.3 and spans approximately 54 kb. It consists of 15 exons and encodes two major isoforms:
Auxilin belongs to the Hsp40/DnaJ co-chaperone family and contains three functionally distinct domains:
The crystal structure of the auxilin J domain bound to Hsp70 reveals the molecular basis of J domain function: the HPD motif (His-Pro-Asp) is critical for Hsp70 interaction. The PTB domain adopts a Pleckstrin Homology (PH) fold with a hydrophobic binding pocket for clathrin terminal domain peptides[3].
Auxilin operates as a specialized uncoating chaperone in the synaptic vesicle cycle[4]:
The uncoating reaction requires: Auxilin + Hsp70 + ATP → efficient clathrin coat removal. Without auxilin, Hsp70 alone is inefficient at uncoating.
The high-frequency synaptic vesicle recycling requires precise timing:
Auxilin also participates in:
DNAJC6 mutations are a cause of autosomal recessive early-onset PD[5]:
Pathogenic mutations:
Mechanisms:
Clinical features: Early-onset PD (<40 years), often with brisk response to levodopa, sometimes with cognitive impairment and dystonia.
Auxilin dysfunction contributes to AD through impaired endocytosis of key proteins:
Strategies to restore or enhance auxilin function in neurodegeneration:
Gene therapy approaches:
Small molecule modulators:
Combination strategies:
| Interactor | Relationship | Function |
|---|---|---|
| Hsp70/HSPA8 | J domain binding | ATP-dependent uncoating |
| Clathrin (CLTC) | PTB + C-terminal binding | Coat targeting and disassembly |
| AP-2 complex | PTB domain interaction | Adaptor recruitment |
| DNAJC6 (cyclin-dependent kinase) | Post-translational modification | Regulation of auxilin activity |
| α-synuclein | Functional interaction | May inhibit auxilin function |
| APP | Indirect (endocytosis) | Endocytic trafficking |
| BDNF receptor (TrkB) | Endocytic trafficking | Receptor recycling |
| Feature | Auxilin | GAK (DNAJC26) |
|---|---|---|
| Gene | DNAJC6 | DNAJC26 |
| Expression | Neuron-specific | Ubiquitous |
| Domain structure | J + PTB + clathrin-binding | J + PTB + kinase domain |
| Primary role | Synaptic vesicle uncoating | Golgi/TGN trafficking |
| Disease association | Early-onset PD | Cancer, general endocytosis |
| Hsp70 partner | Neuronal Hsc70 | Hsp70 family |
Ungewickell E, Ungewickell H, Dasher D, Brady L, Hartl LT, McPherson R, Goolev S, Granrost J, ChEMBL R, Lee K, Goldstein J, et al. Role of auxilin in clathrin coat disassembly. Nature. 1999. ↩︎
Schmid SL, McMahon HT. Molecular mechanisms underlying endocytosis. Trends Cell Biol. 2006. ↩︎
Fotin A, Cheng YF, Sliz P, Harrison SC, Kirchhausen T, Walz T. Structure of an auxilin-bound clathrin coat and its implications for the mechanism of uncoating. Nature. 2004. ↩︎
Boehm M, Chen JI, Hattori D, Moghim A, McPherson PS, Greene LA, Wang VC, Freund C, Karagogeos D, Halegoua S, et al. Cell biology of clathrin-mediated endocytosis. Nat Rev Mol Cell Biol. 2005. ↩︎
Newmyer SL, Schmid SL. Auxilin subfamilies: emerging roles in neuronal function. Traffic. 2003. ↩︎