| Domain Name | Function | Key Features | Role in Disease |
|---|---|---|---|
| J-domain (C-terminal DnaJ domain) | Recruits and activates HSC70/HSPA8 to drive ATP-dependent disassembly of clathrin coats from newly formed clathrin-coated vesicles; this is the core catalytic co-chaperone step in auxilin-mediated uncoating. | Conserved DnaJ/Hsp40-family J-domain with essential HPD motif; stimulates HSC70 ATPase activity; pathogenic human R927G mutation lies in this region and impairs the HSC70-coupled uncoating function; Drosophila homolog R1119G models the same defect (pqac-00000000, pqac-00000003, pqac-00000004, pqac-00000007) | Strongly implicated in PARK19. Missense mutation R927G and truncating alleles that remove or disrupt the C-terminal region impair clathrin uncoating, causing synaptic vesicle recycling defects, synaptic dysfunction, and juvenile/early-onset parkinsonism (pqac-00000000, pqac-00000003, pqac-00000007) |
| PTEN-like domain | Binds phosphoinositide-containing membranes and helps target auxilin to endocytic intermediates during clathrin-mediated endocytosis, coupling membrane lipid state to uncoating. | PTEN-like region is not described as a catalytic lipid phosphatase here; instead it contains a motif for mono-phosphoinositide binding and is proposed to promote membrane recruitment during CME, functionally linking auxilin to PI(4,5)P2/Synaptojanin-regulated membrane remodeling (pqac-00000000, pqac-00000006) | Disease-associated mutations that truncate auxilin upstream of the J-domain likely also remove or destabilize this membrane-targeting region, reducing productive recruitment to coated vesicles and worsening endocytic failure in PARK19 (pqac-00000000, pqac-00000007) |
| C2 domain / Tensin-type C2 region | Likely contributes to membrane association and spatial positioning of auxilin at endocytic membranes, supporting access to clathrin-coated vesicles at presynaptic terminals. | UniProt/domain annotation identifies a C2-domain superfamily/Tensin_C2-like module; C2 domains commonly mediate phospholipid-dependent membrane interactions. Although not deeply dissected in the retrieved papers, the annotated architecture is consistent with synaptic membrane localization during CME (pqac-00000001, pqac-00000004) | No domain-specific zebrafish or human pathogenic variant was directly functionally resolved in the retrieved recent literature, but disruption of N-terminal targeting architecture would be expected to impair presynaptic localization and thereby clathrin uncoating efficiency (pqac-00000001, pqac-00000004) |
| Clathrin-binding domain (CBD) | Binds clathrin cages/coated vesicles and positions auxilin on the clathrin lattice so the J-domain can recruit HSC70 for uncoating. | Located between the PTEN-like region and J-domain in auxilin domain maps; directly linked to the final stage of CME, where auxilin binds engulfed clathrin-coated vesicles before coat removal; works together with membrane-binding regions and the J-domain to couple vesicle recognition to uncoating (pqac-00000000, pqac-00000003, pqac-00000005) | Truncating PARK19 mutations such as Q789X/Q846X are expected to abolish or severely compromise this region and downstream uncoating machinery, leading to accumulation of clathrin-coated vesicles, depletion of synaptic vesicles, and dopaminergic vulnerability (pqac-00000000, pqac-00000005, pqac-00000007) |


*Table: This table summarizes the major annotated domains of DNAJC6/auxilin and how each contributes to clathrin uncoating during synaptic vesicle recycling. It also links specific domains and mutations to PARK19 pathogenesis, which is useful for interpreting functional annotation of zebrafish dnajc6.*