4 diseases explained at one blow said the protein chemist — part 1

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.

Have a look at this

https://cbm.msoe.edu/teachingResources/proteinStructure/secondary.html

If you can tell me how to get a picture like this into a WordPress post please make a comment.

The important point is that hydrogen bonds between the amide hydrogen of one amino acid and the carbonyl group of another hold the alpha helix and the beta pleated sheet together.

Enter proline : p//en.wikipedia.org/wiki/Proline.  Proline when not embedded in a protein has a hydrogen on the nitrogen atom in the ring.  When proline is joined to another amino acid by a peptide bond in a protein, the hydrogen on the nitrogen is no longer present.  So the hydrogen bond helping to hold the two structures (alpha helix and beta sheet) is no longer present at proline, and alpha helices and beta sheets containing proline are not has stable.  Prolines after the fourth amino acid of the alpha helix (e. g. after the first turn of the helix) produce a kink.  The proline can’t adopt the alpha helical configuration of the backbone and it can’t hydrogen bond.

But it’s even worse than that (and this observation may even be original).  Instead of a hydrogen bonding to the free electrons of the oxygen in the carbonyl group you have the two electrons on the nitrogen jammed up against them.  This costs energy and further destabilizes both structures.

Being a 5 membered ring which contains the alpha carbon of the amino acid, proline in proteins isn’t as flexible as other amino acids.

This is why proline is considered to be a helix breaker, and is used all the time in alpha helices spanning cellular membranes to cause kinks, giving them more flexibility.

There is much more to come — liquid liquid phase separation, prion like domains, low complexity sequences, frontotemporal dementia with ALS, TDP43, amyloid, Charcot Marie Tooth disease and Alzheimer’s disease.

So, for the present stare at the link to the diagram above.