How flat can a 100 amino acid protein be?

Alpha-synuclein is of interest to the neurologist because several mutations cause Parkinson’s disease or Lewy Body dementia.  The protein accumulates in the Lewy Bodies of these diseases.  These are concentric hyaline inclusions over 15 microns in diameter found in pigmented brain stem nuclei (substantia nigra, locus coeruleus).

The protein contains 140 amino acids.  It is ‘natively unfolded’ meaning that it has no ordered secondary structure (alpha helix, beta sheet).  No one is sure what it does.  Mouse knockouts are normal, so the mutations must produce something new.

Alpha-synuclein can form amyloid fibrils, which are basically stacks of pancakes made of flattened segments of proteins one on top of the other.

Would you believe that the 100 amino terminal amino acids of alpha-synuclein can form an absolutely flat structure.  Well it does and there are pictures to prove it in PNAS vol. 117 pp. 20305 – 20315 ’20.  Here’s a link if you or your institution has a subscription — https://www.pnas.org/content/pnas/117/33/20305.full.pdf.

This isn’t the usual alpha-synuclein, as it was chemically synthesized with phosphorylated tyrosine at amino acid #39.  Who would have ever predicted that 100 amino acids could form a structure like this?  I wouldn’t. The structure was determined by cryoEM and all the work was done in China.  Very state of the art world class work.  Bravo.

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Comments

  • Mark Thorson  On September 4, 2020 at 5:45 pm

    I thought amyloid fibrils were made out of amyloid-beta. Googling indicates it’s both amyloid-beta and alpha-synuclein. I haven’t found anything that shows what sort of structure it has. If alpha-synuclein is involved, I wonder if cholesterol is also in there, because it’s also a big flat molecule.

  • luysii  On September 10, 2020 at 9:32 pm

    I’m embarrassed by the delay in responding. Apologies ! !

    Lots of different proteins can form amyloid among them the Abeta peptide and alpha-synuclein. Neurologists also do battle with hereditary amyloid polyneuropathy, due to mutations in transthyretin (formerly called prealbumin). 6 years age 100 different neuropathy causing mutations in transthyretin were known. The protein is a tetramer of 127 amino acids.

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