April 20, 2013

April 20, 2013
Close-up of Enzyme Linked to Rapid Aging Disease


Welcome to another day in my life. Today is Saturday and I hope you have had a beary safe and great week. I know there have been two different tragedies in our country and a stressful time for many. It has also been a very busy week for Dab the AIDS Bear.

I think most people do not like aging. Unfortunately, some people start premature aging at a very young age. So today I will blog about something I just read on that issue.

I’d like to tell you about a rare genetic disease: Hutchinson-Gilford progeria syndrome, also called progeria. Though you may not recognize the name, you may well have seen pictures of children with this fatal premature aging disease. By 18-24 months, apparently healthy babies stop growing and begin to lose their hair. They develop wrinkled skin and joint problems and they suffer many other conditions of old age. Though their mental development is entirely normal, they often die of heart disease or stroke by age 12 or 13.

A decade ago, a research lab helped discover the cause of progeria: a mutation in the lamin-A gene [1]. Just a single letter substitution in the genetic code (C to T) creates a toxic version of the protein. The abnormal protein is missing a segment, and is no longer digestible by an enzyme called ZMPSTE24—essentially a molecular scissors. Without that final snip, the lamin-A protein causes molecular havoc.More recently, children who are completely missing the ZMPSTE24 enzyme have been identified, and they have an even more severe form of progeria called “restrictive dermopathy”. Many questions remain but now we are able to get a close up of ZMPSTE24 and understand how, and where, it normally modifies lamin-A.

Using x-ray crystallography, a team based at the UK’s University of Oxford figured out the enzyme’s molecular structure [2, 3]. A cross section of the 3D structure (seen above) reveals a cavernous inner chamber where the authors believe the final snip of lamin-A takes place. It also shows us how mutations in ZMPSTE24, which inhibit lamin-A processing, can also lead to these rare aging disorders.

Knowing ZMPSTE24’s structure will help us better understand its clipping functions. It could also shed light on how this enzyme works in the normal aging processes—as well as in the accelerated aging of progeria. Ultimately, we hope it will also inform drug development for this devastating disease.

Hope you have a beary safe and great Saturday!

Until we meet again; here's wishing you health, hope, happiness and just enough.

big bear hug,



Daddy Dab