Researchers for years thought that tau was a natively unstructured protein. Then how in the world do its supposedly disordered monomers give rise to the orderly stacks of tau molecules seen in tau fibrils? Using chemical cross-linkers to freeze amino acids in space, researchers led by Nikolay Dokholyan of Penn State College of Medicine in Hershey and Christoph Borchers of McGill University in Montreal claim that soluble tau can adopt a compact, globular form. What’s more, despite tau’s constant shape-shifting, its third and fourth microtubule-binding domains form persistent β-strands akin to those found in fibrils, according to the study, published October 15 in Structure. This suggested that even in its loosey-goosey soluble state, tau is poised to assume a pathological formation.

  • Tau can be globular, according to a structure based on cross-linkers.
  • Its microtubule binding domains comprise β-strands.
  • Phosphorylation could expose the strands, prompting aggregation.

Other researchers affirmed the importance of using new approaches to learn more about the structure of soluble tau, but also warned that the technique these authors used is poorly suited to intrinsically disordered proteins (IDPs).

By definition, IDPs such as tau adopt a range of conformations in solution, making it difficult to characterize any one of them. To take snapshots of connections between amino acids in such proteins, Borcher and colleagues developed a technique that goes by the mouthful “cross-linking data as constraints in discrete molecular dynamics simulations" (CL-DMD). In short, they developed a panel of photoreactive cross-linking agents, some with very short spacers, to permanently hitch interacting residues spread throughout a given protein (Brodie et al., 2015; Brodie et al., 2017). Then, using mass spectrometry followed by computational wizardry to map those connections, they pieced together numerous conformations. In this way, the researchers solved structures of FK-506 binding protein, which is laden with β-sheets, and of another infamously disordered protein, α-synuclein (Brodie et al., 2019). 

Molten Globule. CL-DMD uses cross-linkers of varying lengths to lock amino acid contacts in tau (top). Mapping those contacts predicted the predominant structure of soluble tau to be a compact globule (colored ribbons) containing β-strands (orange and red). Other potential conformations are gray. [Courtesy of Popov et al., Structure, 2019.]

Applying the technique to full-length 2N4R tau, co-first authors Konstantin Popov of the University of North Carolina, Chapel Hill, and Karl Makepeace of the University of Victoria in British Columbia, Canada, identified an ensemble of compact, globular structures with variations in their amino acid contacts. The so-called “molten globular” state of the protein jibes with its known disorder. However, within the shape-shifting globule, the researchers also found persistent, defined structures. In particular, the third and fourth microtubule-binding domains together formed seven of the eight β-strands previously pegged by cryo-electron microscopy as the core of tau fibrils isolated from a person with AD (Jul 2017 news). Notably, that AD structure comprised a mix of 3R and 4R tau isoforms, whereas this soluble structure was pure 4R.

A distinctive loop, critical for forming the C-shaped protofilaments in fibrils, was also present within the soluble structure. Along with surrounding β-strands 4–7, it was buried deep in the globule. The researchers speculated that a transient opening of the structure might expose these β-strands to neighboring tau molecules, setting off a cascade of oligomerization. Hypothetically, phosphorylation of any of several residues in the region could expose the hidden strands, they wrote.

Several researchers contacted by Alzforum found the data unconvincing, cautioning that the information in the identified cross-links is insufficient to simulate structural constraints in a 400-residue floppy tau. Confirmation by other techniques, such as NMR, would be needed, they wrote.—Jessica Shugart


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News Citations

  1. Tau Filaments from the Alzheimer’s Brain Revealed at Atomic Resolution

Paper Citations

  1. . Isotopically-coded short-range hetero-bifunctional photo-reactive crosslinkers for studying protein structure. J Proteomics. 2015 Apr 6;118:12-20. Epub 2014 Sep 2 PubMed.
  2. . Solving protein structures using short-distance cross-linking constraints as a guide for discrete molecular dynamics simulations. Sci Adv. 2017 Jul;3(7):e1700479. Epub 2017 Jul 7 PubMed.
  3. . Conformational ensemble of native α-synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations. PLoS Comput Biol. 2019 Mar;15(3):e1006859. Epub 2019 Mar 27 PubMed.

Further Reading


  1. . Dynamical roles of metal ions and the disulfide bond in Cu, Zn superoxide dismutase folding and aggregation. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19696-701. Epub 2008 Dec 3 PubMed.

Primary Papers

  1. . Insight into the Structure of the "Unstructured" Tau Protein. Structure. 2019 Nov 5;27(11):1710-1715.e4. Epub 2019 Oct 15 PubMed.