Nectin-4 (gene name PVRL4, poliovirus receptor-like 4) is a 66 kDa type I transmembrane glycoprotein belonging to the Nectin family of Ig superfamily proteins. The Latin word necto means “to connect”, indicating the role of nectins in Ca2+‑independent cell-cell adhesion. Nectin-4 forms homodimers in cis, followed by interactions in trans with Nectin-1 or -4. Human Nectin-4 mRNA is normally expressed in the placenta, especially in endothelial cells, while in the mouse it is found in the embryo, lung, testis and brain. Human Nectin-4 cDNA encodes 510 amino acids (aa), including a 31 aa signal sequence, a 318 aa extracellular domain (ECD), a 21 aa transmembrane segment (TM), and a 140 aa cytoplasmic region. Nectin ECDs contain three Ig-like domains: an N‑terminal V-type that mediates ligand binding, and two C2-type. One Nectin‑4 isoform lacks aa 412-436 in the cytoplasmic domain (1). In many human ductal breast or non-small cell lung carcinomas, Nectin‑4 is upregulated and a soluble 43 kDa form is found in the plasma. This form is generated from the membrane protein via the action of TACE/ADAM-17. The extracellular domain of human Nectin-4 shares 91%, 92%, 93%, 91% and 90% amino acid sequence homology with the corresponding regions of mouse, rat, canine, porcine and bovine Nectin-4, respectively. In forming adherens junctions, trans interactions of Nectin-4 initiate cell-cell interactions and recruit intracellular cadherins through afadin and other junctional proteins. These interactions organize the actin cytoskeleton, strengthen attachment to basement membrane and promote further cell-cell connections. In humans, mutation of Nectin-4 has been correlated with ectodermal dysplasia-syndactyly syndrome, indicating a role for Nectin-4 in human development.
Human NEDD8 shares 60% amino acid sequence identity to ubiquitin. The only known substrates of NEDD8 modification are the cullin subunits of SCF ubiquitin E3 ligases. The NEDDylation of cullins is critical for the recruitment of E2 to the ligase complex, thus facilitating ubiquitin conjugation. NEDD8 modification has therefore been implicated in cell cycle progression and cytoskeletal regulation.
Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber. May additionally cooperate with the neuronal intermediate filament proteins PRPH and INA to form neuronal filamentous networks.
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