p(HGNC:MAPT, pmod(Ph, Ser, 324))

Entity

Name

MAPT

Namespace

hgnc

Namespace Version

20180906

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/hgnc-names.belns

Tau Biochemistry Section of NESTOR

Tau Modifications Sections of NESTOR

We therefore phosphorylated full-length Tau by MARK2. The downfield chemical shift of phosphorylated residues (Fig. 4a) is in agreement with previous reports and confirms phosphorylation at S262, S293, S305, S324, S356, and S416 PubMed:29215007

Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation-phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function. PubMed:28760828

HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6). PubMed:28760828

Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation-phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function. PubMed:28760828

While residues Ser-262, Ser-324, and Ser-356 were completely phosphorylated, Ser-293 in the second repeat was only 84% phosphorylated (Table 1). Furthermore, four non-KXGS phosphorylation sites were detected, two within the repeat domain (Ser-305 in R2 and Ser-352 in R4) and two more at the C-terminus (Ser-413 and Ser-416) (Figure 1B,C). Of these, Ser-305 was 66% phosphorylated and Ser-352, Ser-413, and Ser-416 were ∼45−58% phosphorylated (Table 1). Using wild-type MARK2cat at 25 °C and pH 6.8, the same phosphorylation sites were observed. The three primary sites, Ser-262, Ser-324, and Ser-356, were still completely phosphorylated. PubMed:24251416

The NMR experiments demonstrate that MARK2- phosphorylation of Tau attenuates its binding to F-actin. Consistent with a reduced affinity, MARK2-phosphorylated Tau failed in bundling actin filaments (Fig. 4e) PubMed:29215007

The NMR experiments demonstrate that MARK2- phosphorylation of Tau attenuates its binding to F-actin. Consistent with a reduced affinity, MARK2-phosphorylated Tau failed in bundling actin filaments (Fig. 4e) PubMed:29215007

The lysine-isoleucine-glycineserine motif (KIGS) or lysine-cysteineglycine-serine motif (KCGS) motifs in the repeat domain (S262, S293, S324, S356) can be phosphorylated by MARK, PKA, SAD kinases, CaMKII and p70S6K, which strongly reduces the tau microtubule interactions (36, 74, 96), [note that phosphorylation at these sites also inhibits tau aggregation, illustrating an analogous role for the repeat domain in the physiological and pathological functions of tau (106)]. PubMed:17493042

The lysine-isoleucine-glycineserine motif (KIGS) or lysine-cysteineglycine-serine motif (KCGS) motifs in the repeat domain (S262, S293, S324, S356) can be phosphorylated by MARK, PKA, SAD kinases, CaMKII and p70S6K, which strongly reduces the tau microtubule interactions (36, 74, 96), [note that phosphorylation at these sites also inhibits tau aggregation, illustrating an analogous role for the repeat domain in the physiological and pathological functions of tau (106)]. PubMed:17493042

Our findings indicate that several acetylation sites in tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with Alzheimer's disease. These findings uncover a novel acetylation-phosphorylation switch at Lys-321/Ser-324 that coordinately regulates tau polymerization and function. PubMed:28760828

HDAC6 inhibition leads to a significant reduction in tau levels as detected by the human tau-specific antibody E1 (Fig. 6 (a and c) and supplemental Fig. S6). We also observed a striking decrease in phosphorylation at Ser-324, which was statistically significant even when normalizing to E1 to control for the reduction in tau levels (Fig. 6 (a and b) and supplemental Fig. S6). PubMed:28760828