crossing of htau mice, which express non-mutant human tau isoforms and represent a model of tauopathy relevant to Alzheimer's disease, with Nmnat1 transgenic and knockout mice. In the resulting offspring until the age of 6 months, overexpression of NMNAT1 ameliorates the early deficit in food burrowing characteristic of htau mice. At 6 months of age, htau mice do not show neurodegenerative changes in both the cortex and hippocampus, and these are not induced by downregulating NMNAT1 levels. Modulating NMNAT1 levels produces a corresponding effect on NMNAT enzymatic activity but does not alter NAD levels in htau mice
Golgi fragmentation in cultured dorsal root ganglion neurons results in caspase dependent axon degeneration and neuronal cell death. NMNAT2 depletion in these neurons causes Golgi fragmentation and caspase dependent axon degeneration. NMNAT2 depletion does not cause ATP loss in the axons. Cytosolic Nmnat1 overexpression inhibits the axon degeneration induced by Golgi fragmentation or NMNAT2 depletion
NMNAT serves as a chaperone of phosphorylated Tau to prevent its amyloid aggregation in vitro as well as mitigate its pathology in Drosophila tauopathy models overexpressing human Tau. NMNAT adopts its enzymatic pocket to specifically bind the phosphorylated sites of Tau, which can be competitively disrupted by the enzymatic substrates of NMNAT. NMNAT serves as a cochaperone of Hsp90 for the specific recognition of phosphorylated Tau over Tau
NMNAT shows strong interaction with phosphorylated truncated Tau protein. The binding affinity of NMNAT3 to phosphorylated Tau is about one order of magnitude higher than that to Tau.The phosphorylated Ser residues of Tau are the primary binding sites. Substrates (i.e. NMN and ATP) and the chaperone client phosphorylated Tau share the same binding pocket with a partial overlap at the phosphate-binding site
residue Asp110 is thought to either hydrogen bond with the adenosine monophosphate during the adenylyltransferase reaction or help with essential Mg+2 coordination during catalysis, the residue has an essential function
residue Asp110 is thought to either hydrogen bond with the adenosine monophosphate during the adenylyltransferase reaction or help with essential Mg+2 coordination during catalysis, the residue has an essential function
the enzyme has a unique 310 helix that locks the active site in an over-closed conformation. This renders the enzyme inactive as it is topologically incompatible with substrate binding and catalysis. The enzyme contains the signature motifs GXFXPX(H/T)XXH and SXTXXR mainly implicated in ATP binding. Mechanistic modelling, overview
the enzyme has a unique 310 helix that locks the active site in an over-closed conformation. This renders the enzyme inactive as it is topologically incompatible with substrate binding and catalysis. The enzyme contains the signature motifs GXFXPX(H/T)XXH and SXTXXR mainly implicated in ATP binding. Mechanistic modelling, overview
the enzyme has a unique 310 helix that locks the active site in an over-closed conformation. This renders the enzyme inactive as it is topologically incompatible with substrate binding and catalysis. The enzyme contains the signature motifs GXFXPX(H/T)XXH and SXTXXR mainly implicated in ATP binding. Mechanistic modelling, overview