Neurofilament protein synthesis and phosphorylation

Neurofilament proteins, a major intermediate filament component of the neur onal cytoskeleton, are organized as 10 nm thick filaments in axons and dend rites. They are large, abundantly phosphorylated proteins with numerous pho sphate acceptor sites, up to 100 in some cases, organized as numerous repea t motifs. Together with other cytoskeletal components such as microtubules, MAPs, actin and plectin-like linking molecules, they make up a dynamic lat tice that sustains neuronal function from neuronal "birthday" to apoptotic cell death. The activity of the neuronal cytoskeleton is regulated by phosp horylation, dephosphorylation reactions mediated by numerous associated kin ases, phosphatases and their regulators. Factors regulating multisite phosp horylation of NFs are topographically localized, with maximum phosphorylati on of NF proteins consigned to axons. Phosphorylation defines the nature of NF interactions with one another and with other cytoskeletal components su ch as microtubules, MAPs and actin. To understand how these functional inte ractions are regulated by phosphorylation we attempt to identify the releva nt kinases and phosphatases, their specific targets and the factors modulat ing their activity. As an initial working model we propose that NF phosphor ylation is regulated topographically in neurons by compartment-specific mac romolecular complexes of substrates, kinases and phosphatases. This implies that axonal complexes differ structurally and functionally from those in c ell bodies and dendrites. Such protein assemblies, by virtue of conformatio nal changes within proteins, facilitate ordered, sequential multisite phosp horylations that modulate dynamic cytoskeletal interactions.