Defining Minimal Binding Regions in Regulator of Presynaptic Morphology 1 (RPM-1) Using Caenorhabditis elegans Neurons Reveals Differential Signaling Complexes

PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2

“…2). This observation expands upon prior work showing RPM-1 and FSN-1 form a ubiquitin ligase complex that regulates axon termination (21,38,39). Our findings now provide the first in vivo biochemical evidence that RPM-1/FSN-1 ubiquitin ligase activity is likely to occur locally at axon termination sites.…”

“…Previous in vitro biochemistry using HEK 293 cells and in vivo biochemistry from transgenic animals showed that C. elegans RPM-1 binds the F-box protein FSN-1 via three domains in RPM-1 called FBD1, FBD2 and FBD3 (38,39). We tested if human PAM/MYCBP2 relies upon a similar conserved mechanism to bind the human F-box protein FBXO45.…”

“…At present, we have the best understanding of how C. elegans RPM-1 forms a complex with FSN-1. In vitro biochemistry using 293 cells and in vivo biochemistry from the worm nervous system indicate that RPM-1 contains multiple FSN-1 binding domains (FBDs) that interact with FSN-1 (38,39). It remains unknown if a similar biochemical mechanism underpins assembly of ubiquitin ligase complexes formed by other PHR proteins, including human PAM.…”

Roles of the HUWE1 ubiquitin ligase in nervous system development, function and disease

“…Subsequent studies in C. elegans combined eel-1 (lf) mutants with enhancer genetics to explore how EEL-1 affects axon development. The sensitizing genetic background used involved mutants for components of a highly conserved, atypical Skp/Cullin/F-box (SCF) ubiquitin ligase complex that consists of the RPM-1 E3 ubiquitin ligase and the F-box protein FSN-1 [31][32][33][34]. The RPM-1/FSN-1 ubiquitin ligase complex is an important regulator of axon termination in C. elegans [35,36], and functions as both a ubiquitin ligase and a signaling hub to affect numerous downstream signaling pathways [31,[37][38][39][40][41][42].…”

Degradation for better survival? Role of ubiquitination in epithelial morphogenesis

“…A RING‐domain neuronal E3 ligase, presynaptic morphology 1 (RPM‐1) is evolutionarily conserved [as peptidylglycine alpha‐amidating monooxygenase (PAM) in Homo sapiens and highwire (Hiw) in Drosophila melanogaster ] and is essential for short‐term learning in Caenorhabditis elegans (Giles et al, ). RPM‐1 interacts with the F‐box/SPRY domain‐containing protein 1 (FSN‐1) and SkpA to form a SCF‐E3 ligase complex, which binds to the microtubule binding protein ribonucleic acid export 1 (RAE‐1) to regulate synapse formation and axonal maintenance (Brace et al, ; Baker & Grill, ). In addition, a cofactor, RAE‐1 binds to the C terminus of the Ub ligase, Hiw to inhibit its degradation in Drosophila melanogaster neurons (Tian et al, ).…”