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Computer Modeling Provides Insight into Overactive FOP Receptor Switch

ACVR1, a bone morphogenetic protein receptor, is a
switch that determines the fate of cells. In individuals who have
FOP, a single misspelled letter in one of the two copies of the
ACVR1 gene causes the ACVR1 switch to be made incorrectly.
That single misspelled letter causes the ACVR1 switch to send a
signal to the inside of the cell telling it to make a new bone where
it should not. As we just learned, factor F, a protein that interacts
with the switch, acts like an armed guard to protect the switch and
keep it shut off until it is properly activated by a BMP molecule.
In the presence of an FOP mutation, factor F (the armed guard)
cannot properly bind to the broken ACVR1 switch and the switch
is unprotected and active even in the absence of BMP.

But, why exactly does factor F not bind properly to
the mutant receptor? Dr. Jay Groppe, a biochemist and x-ray-
crystallographer from Baylor College of Dentistry in Dallas, has
used computer modeling to predict the structure of the normal
and mutant ACVR1 receptor at the atomic level in order to
determine why factor F can not bind properly to the
mutant receptor. Dr.Groppe, supported in part by a
Developmental Grant from The Center for Research in FOP
and Related Disorders, predicts that a previously unidentified
pocket within the normalACVR1 receptor is critically disrupted
by the FOP mutation. Dr. Groppe's studies further predict
that the FOP mutation creates a pH-sensitive switch that
regulates whether or not factor F will properly bind to
the mutant receptor. The model shows that a more
acidic environment (such as might be encountered in an
FOP flare-up) might disable the mutant switch (but not the
normal switch) and make it impossible for factor F to bind
properly. In other words, in an acidic environment, the
mutant switch might be much more vulnerable to being
triggered and creating an atomic explosion (an FOP flare-

DillyYang, Qi Shen, M.D., Ph.D., and Meiqi Xu review
experimental data in the FOP Laboratory

This important theoretical modeling of the FOP switch
was described in a major paper, entitled "Functional Modeling
of the ACVR1 (R206H) Mutation in FOP," that was published in
the journal Clinical Orthopaedics & Related Research in 2007.
The article explains that if x-ray crystallographic and
biochemical studies (presently underway) prove the existence
of this predicted pH-sensitive switch, it might be possible to
modulate the local pH of cells in an FOP flare-up to suppress or
diminish the extent of heterotopic ossification.