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DNA Polymerase Clamp Loaders

Chromosomal DNA replication requires that DNA polymerases be tethered to ring-shaped sliding clamps that encircle the DNA and allow for high-speed, processive replication. Sliding clamps are loaded onto DNA by the clamp loader complex, a pentameric assembly of proteins of the AAA+ family of ATPases.  

 We want to understand the function and mechanism of clamp loaders in atomic detail. Recent structures of the T4 bacteriophage clamp loader in complex with primer-template DNA and the sliding clamp have suggested a working model for the clamp loader mechanism as shown below (see Kelch et al Science 2011):

Our model predicts that ATP hydrolysis begins at the end of the AAA+ spiral and proceeds in a sequential fashion up the spiral, resulting in the ejection of the clamp loader from the DNA and the closed clamp. Our hypothesis is illustrated in this animation of three consecutive ATP hydrolysis events:

 We will test these models for clamp loader mechanism using a wide array of biochemical, biophysical and structural methods. Understanding the clamp loader mechanism in atomic detail will have important implications for understanding DNA replication as well as the mechanism of related AAA+ protein assemblies. Ultimately, we anticipate using our mechanistic understanding to develop novel nanodevices and small molecule effectors of AAA+ function.