Sea of Hypotheses

the Cluster vs. the Camshaft
G680V Suppressors


he secret to understanding these mutants (I believe) lies in the central role of the Camshaft, described above. In the view shown below, we're looking 'down the pipe' of the Camshaft. On the right in white is position 680 (with its alternating mutant form in purple, G680V). On the left are several suppressors of G680V, most prominently the Cluster (green, with mutant forms shown in blue or cyan). Above is L638 (wild type in white, L638F in cyan). N483 is shown in red (wild type) or orange (N483S, the form that suppresses G680V). The multicolored molecule on the right is ATP. Note how the G680V change would tend to push the Camshaft (red) to the left, while all its suppressors would presumably favor a more rightward location.


ow does this help us? Why might the location of the Camshaft influence the release of Pi? Recall that the Gateway (the presumed bottleneck in the exit of Pi from inside the myosin motor) consists of residues R238 and E459--the latter of which sits on the Camshaft!! Further, as shown below, movement of the Camshaft causes (or at least correlates with) opening of the gateway!. And therein lies our hypothesis: G680V perturbs the positioning of the Camshaft, holding the Gateway shut, while suppressors of G680V, such as the Cluster residues, have the opposing effect on the Camshaft, causing it to favor a position which pries the Gateway open. In the normal scheme of things, the Camshaft would favor a Gateway-closing state when actin was absent, but binding of actin would be transmitted to the Camshaft in such a way as to open the Gateway. In order to make these hypotheses more compelling, we are currently launching an all-out assault on the Camshaft to determine which alterations of it favor open and shut positions at the Gateway and how other parts of the motor influence Camshaft positioning.

What do we intend to do about it?


t present, this one's on hold, pending getting these results published! Potential future directions include characterizing suppressors of cluster mutants (V192F, G240V, L453F...) and testing specific mutations of the CamShaft for their influence on G680V suppression.

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Bruce Patterson
http://research.biology.arizona.edu/myosin