Atypical E3 ubiquitin-protein ligase which specifically mediates ubiquitination of threonine and serine residues on target proteins, instead of ubiquitinating lysine residues (By similarity). Shows esterification activity towards both threonine and serine, with a preference for threonine, and acts via two essential catalytic cysteine residues that relay ubiquitin to its substrate via thioester intermediates (By similarity). Interacts with the E2 enzymes UBE2D1, UBE2D3, UBE2E1 and UBE2L3 (By similarity). Plays a key role in neural development, probably by mediating ubiquitination of threonine residues on target proteins (By similarity). Involved in different processes such as regulation of neurite outgrowth, synaptic growth, synaptogenesis and axon degeneration (By similarity). Required in the visual system for correct fasciculation, targeting and mapping of retinal axons (PubMed:15590740). Acts as a regulator of pteridine synthesis (PubMed:15617681). May play a role in the regulation of the circadian clock gene expression (By similarity). [E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-threonine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-3-O-ubiquitinyl-L-threonine. Protein modification; protein ubiquitination. Localizes to axon shafts and associates with microtubule cytoskeleton. Widely expressed when the visual system begins developing. In the eye, expressed in all cells, including retinal ganglion cells, with no obvious gradient. The PHR domains are compact beta-sandwich folds composed of 11 antiparallel strands and decorated with conserved apical loops. They are likely to play a structural role and mediate interactions with substrates or partners. The tandem cysteine domain region confers threonine specificity and contains the two essential catalytic cysteine residues that relay ubiquitin. It binds four zinc ions in a C5HC7HC2 configuration. Fishes display defects in the projection of retinal axons as well as reduced yellow pigmentation (PubMed:15590740, PubMed:15617681). Mutants show failure of anterior axons to map to the posterior tectum: in wild types, retinal axons from the anterior eye remain unbranched and are fasciculated until reaching the posterior tectum, while in mutants, anterior axons branch in the anterior tectum (PubMed:15590740). The posterior tectum is very sparsely innervated (PubMed:15590740). Defects are also detectable in the dorsoventral axis (PubMed:15590740). Reduced yellow pigmentation is caused by a deficiency of sepiapterin, a yellow pteridine (PubMed:15617681). Belongs to the RING-Cys relay (RCR) family.