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 (PubMed:14729956, PubMed:17901218, PubMed:18031680). Required for the formation of major central nervous system axon tracts (PubMed:17901218, PubMed:18031680). Required for proper axon growth by regulating axon navigation and axon branching: acts by regulating the subcellular location and stability of MAP3K12/DLK (PubMed:18031680). Required for proper localization of retinogeniculate projections but not for eye-specific segregation (PubMed:19371781, PubMed:21324225). Regulates axon guidance in the olfactory system (PubMed:23525682). Involved in Wallerian axon degeneration, an evolutionarily conserved process that drives the loss of damaged axons: acts by promoting destabilization of NMNAT2, probably via ubiquitination of NMNAT2 (PubMed:23665224). Catalyzes ubiquitination of threonine and/or serine residues on NMNAT2, consequences of threonine and/or serine ubiquitination are however unknown (By similarity). Regulates the internalization of TRPV1 in peripheral sensory neurons (PubMed:21098484). May mediate ubiquitination and subsequent proteasomal degradation of TSC2/tuberin (By similarity). Independently of the E3 ubiquitin-protein ligase activity, also acts as a guanosine exchange factor (GEF) for RAN in neurons of dorsal root ganglia (PubMed:26304119). May function as a facilitator or regulator of transcriptional activation by MYC (By similarity). Acts in concert with HUWE1 to regulate the circadian clock gene expression by promoting the lithium-induced ubiquination and degradation of NR1D1 (PubMed:20534529). [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. Interacts with MYC (By similarity). Interacts with TSC2 (tuberin) when TSC2 is in complex with TSC1 (hamartin) (By similarity). Interacts with FBXO45 (PubMed:19398581). Interacts with RAE1 (By similarity). Interacts with CPNE1 (via VWFA domain) and CPNE4 (via VWFA domain) (PubMed:12522145). Interacts with (sumoylated) RANGAP1; interaction with sumoylated RANGAP1 inhibits E3 ubiquitin-protein ligase activity and promotes MYCBP2 translocation to the nucleus (PubMed:26304119). Interacts with RAN (PubMed:26304119). Interacts with ATP13A2; the interaction inhibits the ubiquitination of TSC2 by MYCBP2 (By similarity). Interacts with USP11 (By similarity). Localizes to axon shafts and associates with microtubule cytoskeleton (PubMed:18031680). Translocates to the nucleus following interaction with sumoylated RANGAP1 (PubMed:26304119). Expression is mostly restricted to the nervous system, including expression in motor and sensory axons (PubMed:18031680). During postnatal development, expression is particularly strong in the cerebellum, hippocampus and retina (PubMed:14729956). Lower levels of expression are observed throughout the cerebral cortex (PubMed:14729956). Dynamically expressed in embryonic nervous system from 8.5 dpc through 18.5 dpc (PubMed:14729956, PubMed:18031680). At 10.5 dpc, shortly after the birth of the first motor neurons, highly expressed in the developing motor columns, dorsal root ganglion and newly formed neurons within the dorsal neural tube (PubMed:18031680). As embryos develop to 11.5 dpc, expression levels increase in the dorsal root ganglion and expression in the spinal cord expandes as the number of postmitotic neurons increase (PubMed:18031680). By 12.5 dpc expression is widespread within the spinal cord (PubMed:18031680). 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. Autoubiquitinated. Lethality caused by defects in neuromuscular development (PubMed:17901218). Mice die at birth without taking a breath: phrenic nerves are markedly narrower and contain fewer axons than controls (PubMed:17901218). Mice display incomplete innervation of the diaphragm by the phrenic nerve (PubMed:14729956, PubMed:17901218). Intercostal muscles are completely innervated, but show dysmorphic nerve terminals (PubMed:14729956, PubMed:17901218). Sensory neuron terminals in the diaphragm are abnormal and neuromuscular junctions show excessive sprouting of nerve terminals, consistent with inadequate presynaptic stimulation of the muscle (PubMed:14729956). Embryos display motor axon misprojections and stalling: motor axons are error-prone and wander inefficiently at choice points within embryos (PubMed:18031680). Conditional knockout mice lacking Mycbp2 in the retina, exhibit no gross retinal developmental defects; mutants retain normal retinal lamination, monocular segregation and spontaneous retinal wave activity, but mutant retinal ganglion cells exhibit ipsilateral projection to an improper region of the dorsal lateral geniculate nucleus (dLGN) (PubMed:19371781, PubMed:21324225). Conditional knockout mice lacking Mycbp2 in peripheral sensory neurons display prolonged thermal hyperalgesia: defects are caused by constitutive activation of MAP kinase p38 (Mapk11, Mapk12, Mapk13 and/or Mapk14), leading to inhibit internalization of Trpv1 (PubMed:21098484). Belongs to the RING-Cys relay (RCR) family.