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Insight into the structure of the “unstructured” tau protein

ABSTRACT: Here, we apply a recently-developed approach for de novo protein structure determination based on the incorporation of short-distance crosslinking data as constraints in discrete molecular dynamics simulations (CL-DMD), for the determination of the conformational ensemble of tau protein in solution. The predicted structure may facilitate an understanding of the misfolding and oligomerization pathways of the tau protein.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Karl Makepeace

LAB HEAD: Christoph H. Borchers

PROVIDER: PXD015044 | Pride | 2019-10-08

REPOSITORIES: Pride

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			Action	DRS
	20160620_TauHis_TDIG_monomer_CBDPS-H8-D8100uM_OT_MT.kojak.txt	Txt
	20160620_TauHis_TDIG_monomer_CBDPS-H8-D8100uM_OT_MT.raw	Raw
	20160620_TauHis_TDIG_monomer_CBDPS-H8-D8100uM_OT_TN.kojak.txt	Txt
	20160620_TauHis_TDIG_monomer_CBDPS-H8-D8100uM_OT_TN.raw	Raw
	20160620_TauHis_TDIG_monomer_CBDPS-H8-D81mM_OT_MT_1.kojak.txt	Txt

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Publications

Phosphorylation Increases Persistence Length and End-to-End Distance of a Segment of Tau Protein.

Chin Alexander F AF Toptygin Dmitri D Elam W Austin WA Schrank Travis P TP Hilser Vincent J VJ

Biophysical journal 20160101 2

Intrinsically disordered regions of proteins, which lack unique tertiary structure under physiological conditions, are enriched in phosphorylation sites and in significant local bias toward the polyproline II conformation. The overrepresented coincidence of this posttranslational regulatory signal and local conformational bias within unstructured regions raises a question: can phosphorylation serve to manipulate the conformational preferences of a disordered protein? In this study, we use time-r ...[more]

PMID: 26789759

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Are Mouse Models a surrogate for human disease? A temporal, quantitative and molecular perspective.

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Combinatorial native MS and LC-MS/MS approach reveals high intrinsic phosphorylation of human Tau

Project description:Abnormal changes in the neuronal microtubule-associated protein Tau, such as high phosphorylation and aggregation, are considered hallmarks of cognitive deficits in Alzheimer disease. Abnormal phosphorylation is thought to take place before aggregation, and therefore it is often assumed that phosphorylation predisposes Tau towards aggregation. However, the nature and extent of phosphorylation has remained ill-defined. Tau protein contains up to 85 potential phosphorylation sites (80 Ser/Thr, and 5 Tyr P-sites), many of which can be phosphorylated by various kinases because the unfolded structure of Tau makes them accessible. However, limitations in methods (e.g. in mass spectrometry of phosphorylated peptides, or antibodies against phospho-epitopes) have led to conflicting results regarding the overall degree of phosphorylation of Tau in cells. Here we present results from a new approach, that is based on native mass spectrometry analysis of intact Tau expressed in a eukaryotic cell system (Sf9) which reveals Tau in different phosphorylation states. The extent of phosphorylation is remarkably heterogeneous with up to ~20 phosphates (Pi) per molecule and distributed over 51 sites (including all P-sites published so far and additional 18 P-sites). The medium phosphorylated fraction Pm showed overall occupancies centered at 8 Pi (± 5 Pi) with a bell-shaped distribution, the highly phosphorylated fraction Ph had 14 Pi (± 6 Pi). The distribution of sites was remarkably asymmetric (with 71% of all P-sites located in the C-terminal half of Tau). All phosphorylation sites were on Ser or Thr residues, but none on Tyr. Other known posttranslational modifications of Tau were near or below our detection limit (e.g. acetylation, ubiquitination).

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Integrative Threading of the DNA-PKcs Disordered Region with Crosslinking Restraints

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Structural dynamics of the E6AP/UBE3A-E6-p53 enzyme-substrate complex

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