Powerful Inhibitory Protein Binds Less Effectively to Damaged FOP Receptor Than to Normal Counterpart: Molecular Mechanisms of a Mutant Receptor

Did the assassin work alone? Was there more than one
bullet? Who fired the fatal shot? Conspiracy theories abound.
No, we are not talking about the Kennedy assassination, but
about FOP. How can one misspelled genetic letter cause all that
mischief? Well, actually it doesn't! It has a partner in crime, who
has been booked and charged. The name of the co-conspirator?
Let's call it factor F, or to be more precise, the absence of factor
F, working where it should.

Remember the metaphors from previous years of the
atom bomb, the runaway car, the leaky faucet, the broken garage
door, and the damaged TV remote control? What all of those
metaphors have in common with FOP is a broken switch. But,
in FOP, we have evidence that the switch is broken in a very
special way.

Josef Kaplan, Ph.D., pointing out some
interesting cells to Emily McMillan at the FOP Lab.


The FOP switch is normally protected by an armed guard
who is handcuffed to the switch and prevents it from being
activated except by an explicit presidential order. When the order
comes from the President, the armed guard unlocks the switch so
that it can be activated. Now, suppose that the switch was broken
in such a way that the armed guard could not be handcuffed to it,
and therefore could not protect it from promiscuous activation in
the absence of a presidential order. It might then be possible to
trip the switch accidentally and trigger an explosion of an atom
bomb (an FOP flare-up). Well, in our metaphor, ACVR1 is the
switch, factor F is the armed guard, and BMP is the presidential
order. In FOP, the ACVR1 receptor is broken in such a way that
factor F, the armed guard, can not protect it. As a result, the switch
is always active at a low level when it should be "off," and highly
vulnerable to be triggered when BMP is present. In fact, when
BMP is present, the switch goes "haywire" and triggers an atom
bomb (a flare-up).

Thus, factor F, a protein that interacts with and normally
protects the ACVR1 switch from being activated in the absence
of BMP (a presidential order), also controls access to the switch
on the cell surface. In FOP, due to the single letter mutation in the
FOP gene, factor F, the protein that should normally guard the
switch cannot properly do so. It's like creating nuclear weapons,
but leaving them unguarded - not a good thing!

As the Editors of the journal Cell wrote in a recent
editorial, "Elucidation of molecular mechanisms inevitably
creates exciting new questions and insights into biology and is
a prerequisite for applied research, such as mechanism-based
drug discovery. It is also at the level of molecular mechanisms
that different fields can most easily learn and borrow from each
other, and even sometimes meld." Or, as Albert Einstein said,

"Something deeply hidden had to be behind things."