Neuwald, A. F. (July 2006) Hypothesis: bacterial clamp loader ATPase activation through DNA-dependent repositioning of the catalytic base and of a trans-acting catalytic threonine. Nucleic Acids Res, 34 (18). pp. 5280-90. ISSN 1362-4962 (Electronic)
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Abstract
The prokaryotic DNA polymerase III clamp loader complex loads the beta clamp onto DNA to link the replication complex to DNA during processive synthesis and unloads it again once synthesis is complete. This minimal complex consists of one delta, one delta' and three gamma subunits, all of which possess an AAA+ module--though only the gamma subunit exhibits ATPase activity. Here clues to underlying clamp loader mechanisms are obtained through Bayesian inference of various categories of selective constraints imposed on the gamma and delta' subunits. It is proposed that a conserved histidine is ionized via electron transfer involving structurally adjacent residues within the sensor 1 region of gamma's AAA+ module. The resultant positive charge on this histidine inhibits ATPase activity by drawing the negatively charged catalytic base away from the active site. It is also proposed that this arrangement is disrupted upon interaction of DNA with basic residues in gamma implicated previously in DNA binding, regarding which a lysine that is near the sensor 1 region and that is highly conserved both in bacterial and in eukaryotic clamp loader ATPases appears to play a critical role. gamma ATPases also appear to utilize a trans-acting threonine that is donated by helix 6 of an adjacent gamma or delta' subunit and that assists in the activation of a water molecule for nucleophilic attack on the gamma phosphorous atom of ATP. As eukaryotic and archaeal clamp loaders lack most of these key residues, it appears that eubacteria utilize a fundamentally different mechanism for clamp loader activation than do these other organisms.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Adenosine Triphosphatases chemistry metabolism Amino Acid Sequence Arginine chemistry Bacterial Proteins chemistry metabolism Bayes Theorem Binding Sites Catalysis DNA, Bacterial chemistry metabolism DNA-Binding Proteins chemistry metabolism Enzyme Activation Histidine chemistry Models Molecular Molecular Sequence Data Protein Subunits chemistry metabolism Sequence Alignment Threonine chemistry |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > DNA polymerase bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA replication bioinformatics > computational biology |
| CSHL Authors: | |
| Communities: | CSHL labs > Neuwald lab |
| Depositing User: | CSHL Librarian |
| Date: | July 2006 |
| Date Deposited: | 09 Dec 2011 17:35 |
| Last Modified: | 08 Nov 2017 15:28 |
| PMCID: | PMC1636414 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/22872 |
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