It’s been several years since I last presented a talk on prions to OPIG, so I thought a neat way of getting up to date would be to read “The prion 2018 round tables“. What’s the current understanding and are we any closer to determining a structure of PrPSc?
In short, we now know a lot more than we used to. However this is one of those problems where the more you know, the harder the problem becomes.
There are currently two proposed structures for PrPSc :
- PIRBS – Parallel In-Register Beta Sheets
- β-solenoids
Experiments published in peer-reviewed journals in 2007, 2010 and 2014, performed in different labs and using techniques including site-specific spin labeling as well as solid-state NMR have shown that PIRBS is a likely structure.
Whilst it is enormously difficult to determine the structure of brain-derived PrPSc, subsections of it can be expressed which can be more readily defined. In position 145, a tyrosine to stop codon mutation can be used to provide a truncated PIRBS-shaped PrP fragment. In fact, even this remarkably small fragment (PrP23-144) has been shown to be infectious.
On the other hand, there is strong evidence that PrPSc has a β-solenoid structure. This has been determined by both Cryo-EM and by Solid-State NMR by at least two different research groups. As mentioned in the paper “The 4-rung β-solenoid model agrees with experimental constraints of brain derived PrPSc”
Not being an experimentalist, I’ve got no right or reason to wade in on which structure is more likely. This leaves the question, is what was once a difficult problem now compounded by there being two different strains of PrPSc? Possibly. Our unknown structure(s) of PrPSc form through an unknown post-translational mechanism. But to make a difficult job harder, the paper concludes: “PIRIBS structures might be able to template 4-rung β-solenoids and 4-rung β-solenoids might template PIRIBS amyloids, as was seen in the amyloid seeding assay“.
That’s right, our unknown β-solenoid, may through an unknown mechanism, template an unknown PIRBS structure and via another unknown mechanism, vice versa.
