The p97 molecular machine helps recycle proteins,
you have trillions of this machine in your body.
Inherited mutations of its gene causes fronto-temporal dementia
with typical onset at age 50.
Same mutations cause muscle weakness and a bone disorder.
p97 is seen in aggregated proteins (plaques) found in the brain in
neuro-degenerative diseases like Parkinsons where protein recycling fails.
Disease from p97 mutations is very rare but understanding it may help
explain other dementia diseases, and modulating p97 with drugs could
improve protein recycling.
How does the p97 machine work?
It is made up of 6 copies of the same molecule arranged in a ring.
Each molecule has 3 movable parts (green, blue, pink).
There are two motions.
There are two batteries, ATP molecules (red),
on the interior of each of the 6 copies that drive the two motions.
An inhibitor drug (yellow) blocks the motion of the pink domain.
Often inhibitors block the power source ATP or stick moving parts together but this does neither.
The motion requires some flexibility where the inhibitor binds.
The disease mutation (bright pink) is a change of one amino acid (R155H), about 20 atoms out of 10,000,
on the green N-terminal domain.
The mutation may cause the green and blue domains to hold to each other
tighter or looser.
Interactions with p97 are mostly through the green domain
and any change to it could alter interactions with other proteins.
The p47 adaptor molecule (fragment shown in orange, 1s3s) allows p97 to assist in fusion of membranes
after cell division. This adaptor does not overlap with the mutation site.
The ufd1-npl4 adaptor (npl4 fragment shown in light blue, 2pjh) allows detecting proteins tagged
for recycling (with ubiquitin tags). It also does not overlap the mutation site.
Other adaptors bind to the green domain, possibly in different locations.