Human Nogo-A (also reticulon-4) is a member of the reticulon family of transmembrane proteins. This family is characterized by the presence of a nonsignal sequence-containing N-terminus, a topologically conserved 200 amino acid (aa) C-terminus that contains two transmembrane domains with an ER-retention motif, and a punctate intracellular distribution within the ER that is reminescent of a reticulum (1 - 4). In human, Nogo exists in five isoforms (5 - 7). The full length human form (Nogo-A) is 1192 aa in length and contains a 1018 aa N-terminus, a 21 aa transmembrane segment, a 94 aa connecting “loop”, a second 21 aa transmembrane segment, and a 38 aa C-terminus. Three areas are of particular interest. One is a stretch of 66 aa within the 94 aa connecting loop. This segment is reported to bind to the GPI-linked Nogo receptor/p75 complex on axons and induce growth cone collapse (8 - 10). Two other areas in the N-terminus have also been discovered to have bioactivity (8, 11, 12). Based on rat, aa 57 - 184 in human (aa 59 - 172 in rat) should block fibroblast spreading, while aa 566 - 748 in human (aa 544 - 725 in rat) block neurite outgrowth and block fibroblast spreading (8, 12, 13). The exact topology of Nogo-A is unclear. The N- and C-termini may be extracellular with the “loop” region intracellular, or the situation could be reversed (13 - 15). Alternatively, the loop region and N-terminus may be on the same side of the membrane (3, 8). The four additional isoforms are shorter than Nogo-A (199 aa [Nogo-C], 373 aa [Nogo-B], 392 aa and 986 aa, respectively) (7). Although highly divergent, all contain the same C-terminal stretch, aa 1005 - 1192. Both Nogo-B and C are reported to complex with Nogo-A (16). Notably, Nogo-A is expressed in neurons, endothelial cells. oligodendrocytes, fibroblasts and myoblasts (12, 16 - 18). Human Nogo-A is 78% aa identical to mouse and rat Nogo-A overall, with 98% aa identity in the loop region and approximately 80% aa identity in the aa 566 - 748 segment.
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