PNMA2 (ParaNeoplastic antigen MA2) is a protein initially found as the target of the immune response (autoantibodies) producing a nasty dementing neurologic disease (Paraneoplastic encephalitis). The PNMA2 protein is exclusively expressed in neurons which implies that neurons are using it for something. This is teleological thinking, usually looked down on, but always needed in molecular biology and cellular physiology.
What PNMA2 does is amazing. It forms icosahedral viral capsids which are released from cells (in culture) as nonEnveloped capsids. It isn’t clear if this normally happens in our brains. Probably it doesn’t, and when the capsid somehow gets out of the producing cell or neuron immunological hell breaks loose and autoimmune encephalitis is the result.
PNMA2 is derived from one of the long terminal repeat retrotransposons (LTR retrotransposons), viral remnants that make up 8% of the human genome (https://en.wikipedia.org/wiki/LTR_retrotransposon). This explains why it makes particles that look like viruses. Such particles can contain RNA, so big pharma is interested in them as a way of delivering mRNA drugs.
Totally off topic but yesterday I read a paper about E. Coli DNA gyrase, an amazing enzyme which untangles DNA ( Science vol. 384 pp. 227 – 232 ’24 ).
Here is what it does. If you’ve got some venetian blinds in your home twist it 20 or so times (keeping the ends fixed, and you have the DNA double helix, with two strands winding around each other. Now to read or copy a single strand, you must grab both strands where you want this to happen and pull them apart keeping the ends of the venetian blind fixed. This immediately increases the coiling elsewhere. Since there are only 10 nucleotides/turn of the double helix, copying a gene for a 100 amino acid protein means you are removing 33 twists from the separated strands (and producing new ones elsewhere). The cords of the venetian blind quickly become a tangled mess when this happens. This is where DNA gyrase comes in. It cuts both strands of the DNA double helix, holding on to the cut ends, and slides an intact double helix of the twisted DNA through the cut. Sounds fantastic doesn’t it? Hard to see how evolution could come up with something like this but it did.
The paper contains the following passage toward the end
“A second model based on a sign-inversion reaction wassuggested to describe introduction of (–)SC by this enzyme (28). This model proposed that the enzyme binds to a positive crossover followedby a DNA strand passage through a DNA double-strand break that results in a sign inversion.”
(28) is 28. P. O. Brown, N. R. Cozzarelli,Science206, 1081–1083 (1979).
The paper is 45 years old and has now been shown to be correct. N. R. Cozzarelli is my late good friend and Princeton classmate Nick, and it is very nice to see him honored here.
A few words about Nick. Although Princeton was full of rich kids, they still had the brains to take in someone like Nick whose father was an immigrant shoemaker in Jersey City. Nick worked his way through Princeton waiting on tables in commons (where all Freshmen ate). I can still see the time that some rich preppie jerk gave him a hard time about the service.
Nick got his PhD at Harvard and later became a professor at Berkeley where he did his great work. Nick later edited the Proceedings of the National Academy of Sciences (USA) for 10 years before his very untimely death over 20 years ago from Burkitt’s lymphoma. R. I. P. Nick.
Chemiotics II 