The complete primary structure of the largest neurofilament component, NF-H, has been predicted from mouse and human cDNA and genomic clones. The studies reveal a protein of molecular weight ca. 115,000. A central filament-forming domain structurally typical of all intermediate filaments proteins is present but anomalies are noted which place constraints on the mechanism of NF- H assembly into filaments. The carboxy terminal portion of the protein is extremely long (661 amino acids) by comparison to non- neuronal intermediate components and has a remarkable monotonous highly charged composition. Its most remarkable feature is a tandem repeat of 6 amino acids containing the sequence motif Lys- Ser-Pro which extends for more than one half the length of the carboxy terminus. The Lys-Ser-Pro motif appears 48 times in the mouse NF-H and 43 times in the human NF-H. We, as well as others, have presented evidence that this motif is the target for in vivo kinase and the presence of the copies of the repeat explains the massive axonal phosphorylation of the NF-H. The human NF-H. The human NF-H has three introns, two of which interrupt the coding sequence at identical points to introns and genes encoding the two smaller NF proteins. The third intron interrupts the coding sequence at exactly the same position as introns in non-neural IF proteins. Hence, the NF-H gene bears some striking resemblance to non-neuronal IF genes. Consequently, it is likely that the divergence of the neuronal from the non-neuronal IF lineages evolved from the ancestral IF gene by duplication rather than a RNA mediated transposition event as postulated by others.
