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Sea of Hypotheses |
| As the CamShaft turns...
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ell, you win some and try not to worry too much about the other 95% or so...Recall that
the initial hypothesis was that M486I acted as a suppressor of several actin binding site
mutants (E531Q, P536R, R562H, and delWrinkle) by increasing the tendency of the CamShaft
to bend between amino acids 486 and 487. The key prediction of this hypothesis is that
'bend-promoting' amino acids (Ile, Thr and Val, also possibly Gly and Pro) could act as
suppressors whereas 'helix-promoting' ones such as Ala, Arg, Lys and Leu could not.
The Good News: Glycine can indeed act as a suppressor, satisfying a weak prediction
of the model.
The Bad News: The very FIRST 'lottery-generated' suppressor (of R562H, as it turns
out) is M486A (change to Ala). Since Alanine is perhaps THE BEST amino acid in terms of
generalized helical tendencies, a very strong prediction of the model has been shot down
in very conspicuous flames!
ow what? First and foremost, the original model proposed here must be modified (or
abandoned), since the data fail to match its clearest prediction. We now know that
position 486 can mutate to a suppressor by changing from Met to Ile, Gly or Ala. Is
this the whole list or are there others? We are continuing the Search and should have
a longer list (or know that the list is complete) by ~September 15. The striking thing
about the new suppressors is that they are the two SMALLEST amino acids. This gives
rise to the following modified hypothesis:
- Bending of the CamShaft is still considered the key to suppression
- M486I is still thought to act by increasing 'bendability' of the CamShaft
- M486A suppresses because it truncates the long sidechain of methionine. Imagine that methionine is a piton anchoring the CamShaft to the bulk of the whale (it to properly oriented for this role). Changing to alanine breaks the connection. This doesn't make the CamShaft more bendable per se, but now allows it to bend 'earlier'Ñsuch as at position 483Ñwhich is an asparagine and a very popular amino acid for ends of helices
- M486G may be acting by a combination of both routesÑincreasing bendability and letting go of the 'roof'
o what? The point of making a new model is not to save face but to make new predictions
and test them. So here's round II predictions:
- Valine and Threonine are still predicted to suppress for the original reasons
- Serine and Cysteine may suppress because of smallness
- Proline will suppress unless it renders the Camshaft ALWAYS bent. In this case, it will have a severe mutant phenotype and may be interesting for biochemical characterization
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