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PubMed: 29215007

Title
Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau.
Journal
Nature communications
Volume
8
Issue
None
Pages
1981
Date
2017-12-07
Authors
Riedel D | Cabrales Fontela Y | Zweckstetter M | Kadavath H | Biernat J | Mandelkow E

Evidence 8b68e82ae3
JSON

The analysis reveals that the proline-rich regions P1–P2 and the four pseudo-repeats contribute to the Tau/F-actin interaction

a(HBP:HBP00166) increases complex(a(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 6173c42bc6
JSON

The combined data—(i) competition of binding of Tau to F-actin by cofilin, which interacts with actin’s hydrophobic pocket, and (ii) residue-specific PRE effects in the repeat domain of Tau by preferential MTSSL-labeling of C374 in proximity to the hydrophobic pocket—suggest that Tau binds to the solvent-exposed hydrophobic pocket that is located between subdomains 1 and 3 of actin

a(HBP:HBP00169) positiveCorrelation complex(a(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

a(HBP:HBP00169) positiveCorrelation complex(a(GO:"filamentous actin"), p(HGNC:CFL1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

a(HBP:HBP00169) positiveCorrelation complex(a(MESH:Actins), p(HGNC:CFL1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

complex(a(GO:"filamentous actin"), p(HGNC:CFL1)) positiveCorrelation a(HBP:HBP00169) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

complex(a(GO:"filamentous actin"), p(HGNC:MAPT)) positiveCorrelation a(HBP:HBP00169) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

complex(a(MESH:Actins), p(HGNC:CFL1)) positiveCorrelation a(HBP:HBP00169) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 0b43740597
JSON

Truncation of Tau by caspases and endopeptidases has been suggested to constitute an important pathogenic step in AD

a(MESH:Caspases) increases p(HGNC:MAPT, var("?")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(MESH:Endopeptidases) increases p(HGNC:MAPT, var("?")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, var("?")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, var("?")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence fd83603e9c
JSON

Addition of an equimolar concentration of Tau caused bundling of F-actin (Fig. 1b), although some single filaments remained

p(HGNC:MAPT) increases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence e85bf7321f
JSON

Quantification of the intensity of different bands indicated that ~63% of Tau remained in the supernatant. In addition, ~8% of Tau molecules were bound to single filaments, while ~29% of Tau was found together with actin bundles. The data demonstrate that Tau bundles actin filaments

p(HGNC:MAPT) increases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence f407d1819a
JSON

In addition, K18 was capable of bundling F-actin (Supplementary Fig. 5b)

p(HGNC:MAPT, frag("244_372")) increases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 7f6b396aa2
JSON

Sequential resonance assignment of the peptide (Supplementary Table 3), followed by NOE analysis (Supplementary Fig. 13) and structure calculations (Supplementary Fig. 14) showed that the short peptide folds into an α-helix (residues 259–265) in complex with F-actin that is similar to the one found in Tau(254–290) (Supplementary Fig. 14b)

complex(a(GO:"filamentous actin"), p(HGNC:MAPT, frag("254_268"))) increases bp(MESH:"Protein Conformation, alpha-Helical") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

complex(a(GO:"filamentous actin"), p(HGNC:MAPT, frag("254_290"))) increases bp(MESH:"Protein Conformation, alpha-Helical") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 70c9917503
JSON

In contrast to Tau(254–290), however, Tau(254–268) was not able to bundle F-actin (Supplementary Fig. 5d)

p(HGNC:MAPT, frag("254_268")) decreases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, frag("254_290")) increases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 68193c4990
JSON

To gain insight into the structure, which these segments adopt in complex with F-actin, we used the peptide Tau(254–290), which bundles filaments (Fig. 3a)

p(HGNC:MAPT, frag("254_290")) increases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence aac81e3858
JSON

When compared to the wild-type peptide, Tau(254–290)-L266E showed a decreased STD signal (Supplementary Figure 10c–e), indicating that the mutation attenuated F-actin binding

p(HGNC:MAPT, frag("254_290")) increases complex(a(GO:"filamentous actin"), p(HGNC:MAPT, frag("254_290"))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, var("p.Leu256Glu")) decreases complex(a(GO:"filamentous actin"), p(HGNC:MAPT, frag("254_290"))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 3cc061543a
JSON

In contrast, medium-range NOE cross-peaks, which are specific for secondary structure, were observed for residues ~260 to ~268 and residues ~277 to ~283

p(HGNC:MAPT, frag("260_268")) increases bp(MESH:"Protein Structure, Secondary") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, frag("277_283")) increases bp(MESH:"Protein Structure, Secondary") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 54024ab780
JSON

The analysis suggests that the experimental NOE data witness the formation of helical structure in these regions upon binding to F-actin, but the number of detected restraints is not sufficient to define a unique conformation

complex(a(GO:"filamentous actin"), p(HGNC:MAPT, frag("261_265"))) increases a(HBP:HBP00170) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

complex(a(GO:"filamentous actin"), p(HGNC:MAPT, frag("261_268"))) increases bp(MESH:"Protein Conformation, alpha-Helical") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

complex(a(GO:"filamentous actin"), p(HGNC:MAPT, frag("277_280"))) increases a(HBP:HBP00170) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

complex(a(GO:"filamentous actin"), p(HGNC:MAPT, frag("277_283"))) increases bp(MESH:"Protein Conformation, alpha-Helical") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 9dc655a312
JSON

In some of the other conformers of Tau (254–290), however, residues 261–265 were identified not as α- helix but as 3–10 helix, while residues 277–283 were assigned to α-helix

p(HGNC:MAPT, frag("261_265")) increases a(HBP:HBP00170) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, frag("277_283")) increases bp(MESH:"Protein Conformation, alpha-Helical") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 75cfb08dcd
JSON

Analysis of secondary structure in the lowest energy conformation using STRIDE47, identifies α-helix for residues 261–268 and 3–10 helix for residues 277–280

p(HGNC:MAPT, frag("261_268")) increases bp(MESH:"Protein Conformation, alpha-Helical") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, frag("277_280")) increases a(HBP:HBP00170) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 6a91945bbd
JSON

Tau(292–319) comprises the residues of repeat R2 and R3, which experience strong signal attenuation upon addition of F-actin to full-length Tau (Fig. 1e, f). In agreement with the ability of Tau(292–319) to bind to F-actin, the peptide promotes bundling of actin filaments (Supplementary Fig. 5c)

p(HGNC:MAPT, frag("292_319")) increases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 50f697ba26
JSON

One of these binding partners is cofilin, a 21 kDa eukaryotic protein, which binds to F-actin with a Kd < 0.05 μM33 and results in disassembly of F-actin34, 35. Cryo-electron microscopy further showed that the binding site of cofilin on F-actin is highly similar to its binding site on G-actin (Fig. 2a)32

composite(complex(GO:"filamentous actin"), p(HGNC:CFL1)) decreases complex(GO:"filamentous actin") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 0489db4b52
JSON

In most structures a 3–10 helix was identified for residues 315–318, although in the lowest energy structure residues 315–318 are in α-helical conformation (Supplementary Figure 12c)

p(HGNC:MAPT, frag("315_318")) increases a(HBP:HBP00170) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence afd837d365
JSON

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)

p(HGNC:MAPT, pmod(Ph, Ser, 262)) decreases complex(a(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 262)) decreases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 293)) decreases complex(a(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 293)) decreases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 305)) decreases complex(a(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 305)) decreases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 324)) decreases complex(a(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 324)) decreases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 356)) decreases complex(a(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 356)) decreases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 416)) decreases complex(a(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 416)) decreases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence c8e7b7ec86
JSON

In addition, attachment of a phosphate group to S262 in the peptide Tau (254–284) decreased the affinity of the peptide for F-actin (Supplementary Fig. 1) and lowered the amount of Tau (254–284)-promoted actin bundles (Fig. 4f)

p(HGNC:MAPT, pmod(Ph, Ser, 262)) decreases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MAPT, pmod(Ph, Ser, 262)) decreases complex(a(GO:"filamentous actin"), p(HGNC:MAPT, frag("254_284"))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 0c38dfa34a
JSON

In agreement with a decrease in affinity of Tau(254–290)-L266E for binding to F-actin (Supplementary Fig. 1), the mutant peptide was less efficient in promoting F-actin bundling (Supplementary Fig. 10f)

p(HGNC:MAPT, var("p.Leu256Glu")) decreases bp(GO:"actin filament bundle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence c9be8b6058
JSON

An important class of kinases that phosphorylate Tau at S262 and the other KXGS motifs in the repeat domain are the microtubule-associated protein/microtubule affinity-regulating kinases (MARKs)

act(p(HGNC:MARK2), ma(kin)) increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

act(p(HGNC:MARK2), ma(kin)) increases p(HBP:HBP00098, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 96727a3ad1
JSON

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

p(HGNC:MARK2) increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MARK2) increases p(HGNC:MAPT, pmod(Ph, Ser, 293)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MARK2) increases p(HGNC:MAPT, pmod(Ph, Ser, 305)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MARK2) increases p(HGNC:MAPT, pmod(Ph, Ser, 324)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MARK2) increases p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:MARK2) increases p(HGNC:MAPT, pmod(Ph, Ser, 416)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

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