A brilliant paper [ Science vol. 377 eabn5582 pp. 1 –> 20 ’22 ] explains how changing a single amino acid (proline) to another can cause 4 different diseases, depending on the particular protein it is found in (and which proline of many is changed).
There is so much in this paper that it will take several posts to go over it all. The chemistry in the paper is particularly fine. So it’s back to Biochemistry 101 and the alpha helix and the beta sheet.
A lot of the paper concerns TDP43, a protein familiar to neurologists because it is involved in FTD-ALS (FrontoTemporal Dementia — Amyotrophic Lateral Sclerosis) and ALS itself.
I actually saw a case early in training. I had been taught that ALS patients remained cognitively intact until the end (certainly true in my experience — think of Stephen Hawking), so here was this ALS case who was mildly demented. My education, deficient at that time, so I’d never heard of FTD-ALS, had me writing in the chart “we’re missing something here”. These were calmer times in the medical malpractice world.
TDP43 is a protein with a lot of different parts in its 414 amino acids. There are two regions which bind to RNA (Rna Recognition Motifs { RRMs } ), and a glycine rich low complexity domain at the carboxy terminal end.
TDP43 proteins are found in the neuronal inclusions of ALS (interestingly, these weren’t recognized when I was in training). The low complexity domain of TDP43 aggregates and form fibers. Some 50 different mutations have been found here in patients.
Just this year the cryoEM structure of TDP43 aggregates from two patients with FTD-ALS were described [ Nature vol. 601 pp. 29 – 30, 139 – 143 ’22 ]. It appears to be a typical amyloid structure with all 79 amino acids (from # 282 Glycine to #360 Glutamine) in a single plane. Here’s a link to the actual paper — https://www.nature.com/articles/s41586-021-04199-3. It is likely behind a paywall, but if you can get it, look at figure 2 p. 140, which has the structure. Who would have ever thought that a protein could flatten out this much.
Both structures were from TDP-43 with none of the 24 mutations known to cause FTD-ALS.
But that’s far from the end of the story. The same area of TDP43 can also form liquid droplets (perhaps the precursor of the fibers). But that’s where the brilliant chemistry of [ Science vol. 377 eabn5582 pp. 1 –> 20 ’22 ] comes in.
That’s for next time. After that, I should be finished with Needham and will have time to write about 6 or so of the interesting papers I’ve run across in the past 6 months.
Chemiotics II 