RING finger, H2 subclass, found in the PHR (Pam/Highwire/RPM-1) protein family
The PHR protein family represents an evolutionally conserved family of large proteins including human E3 ubiquitin ligase protein associated with Myc (Pam) and its homologs, Phr1 in mouse, Highwire (HIW) in Drosophila, RPM-1 (regulator of presynaptic morphology 1) in Caenorhabditis elegans, and Esrom in zebrafish. Those proteins are large E3 ubiquitin ligases containing regulator of chromosome condensation (RCC) homology domains (RHD-1 and RHD-2) with inferred guanine exchange factor (GEF) activity, a Myc-binding domain, a B-box zinc finger, and a C-terminal C3H2C3-type RING-H2 finger with E3 ubiquitin (Ub) ligase activity. They play an important role in axon guidance and synaptogenesis. They regulate synapse formation and growth in mammals, zebrafish, Drosophila, and Caenorhabditis elegans, and may control a variety of signaling pathways, including cAMP signaling in mammalian cells, JNK/p38 MAPK signaling in Drosophila and C. elegans, and bone morphogenetic protein signaling in Drosophila. Pam also known as Myc-binding protein 2 (MYCBP2), or Pam/highwire/rpm-1 protein (PHR1), negatively regulates neuronal growth, synaptogenesis and synaptic plasticity by modulating several signaling pathways including the p38 MAPK signaling cascade. It also participates in receptor and ion channel internalization, such as regulating internalization of transient receptor potential vanilloid receptor 1 (TRPV1) in peripheral sensory neurons, as well as duration of thermal hyperalgesia through p38 MAPK. It interacts with neuron-specific electroneutral potassium (K+) and chloride (Cl-) cotransporter KCC2 and modulates its function. Moreover, Pam genetically interacts with Robo2 to modulate axon guidance in the olfactory system. It also associates with tuberous sclerosis complex (TSC) proteins, ubiquitinating TSC2 and regulating mammalian/mechanistic target of rapamycin (mTOR) signaling. Furthermore, Pam is the longest lasting nontranscriptional regulator of adenylyl cyclase activity, and can mediate sustained inhibition of cAMP signaling by sphingosine-1-phosphate. It is also involved in spinal nociceptive processing. Phr1 is an essential regulator of retinal ganglion cell projection during both dorsal lateral geniculate nucleus (dLGN) and superior colliculus (SC) topographic map development. RPM-1 positively regulates a Rab GTPase pathway to promote vesicular trafficking via late endosomes, thereby regulating synapse formation and axon termination. Esrom has E3 ligase activity and modulates the amount of phosphorylated Tuberin, a tumor suppressor, in growth cones. It is required for the formation of the retinotectal projection.
Comment:C3H2C3-type RING-H2 finger consensus motif: C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-H-X2-C-X(4-48)-C-X2-C, where X is any amino acid and the number of X residues varies in different fingers
Comment:A RING finger typically binds two zinc atoms, with its Cys and/or His side chains in a unique "cross-brace" arrangement.
Jiyao W et al.(2023). "The conserved domain database in 2023.",