Structural mechanisms of multimeric atpases
Active Project Grant Awarded Last action
- Award ID
- R35GM156361
- Recipient
-
University Of Massachusetts Medical School UEI MQE2JHHJW9Q8
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,692,871
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date 36% complete
- Place of performance
- Worcester, MA 01655, USA
Award details come from USAspending.gov.
Description
- Abstract
- Structural mechanisms of multimeric atpases the kelch lab studies how multimeric atpases drive the mechanics of biology. These machines facilitate numerous biological pathways, ranging from DNA replication to virus assembly. Despite their strong structural conservation, the mechanisms of multimeric atpases are varied, with some functioning as processive motors and others as molecular switches. How this divergence in mechanism arises from conserved components remains unknown. Here we investigate the structures and mechanisms of two similar atpase machines that demonstrate either processive or switch-like functions. The terminase is an exceptionally powerful and processive motor that pumps DNA into viral capsids. Clamp loaders are 'one-and- done' (non-processive) protein remodeling switches that open the sliding clamp ring and place IT onto DNA for replication and repair. Both of these machines are related pentameric atpases that assemble into ring-like structures, so the stark differences in function are not easily explained by subunit stoichiometry or overall architecture. The kelch lab has been at the forefront of elucidating the structural mechanisms of both clamp loaders and terminases. We determined the molecular organization of the terminase motor, which became the foundation for the past decade in the field. Our structures of clamp loaders in action have provided unprecedented insight into the mechanism of the most conserved components of the replication fork. In both terminases and clamp loaders, transitions between spiral and planar conformations of the atpase domains have been implicated, indicating that motor or switch mechanisms are driven by similar structural changes. Not only have our studies been impactful in their individual fields but, by comparing these two mechanisms, we have laid the groundwork for understanding divergent atpase mechanisms. Our previous studies indicate that the differences in mechanism cannot be easily explained by stoichiometry, overall architecture, or conformational changes of the atpase domains, which implicates timing and coordination of atpase activity in determining function. Thus, we have identified three open questions that are a prerequisite for understanding how nature evolved distinct atpase functions: - how do atpase machines enforce directionality of the reaction? - how do atpases coordinate non-atpase activities? - how do exogenous factors modulate machine function? To address these questions, we have developed a research program that combines structural studies with incisive examination of biochemical activity and biological function. Furthermore, we have assembled a team of collaborators whose expertise complements that of the kelch lab to maximize the scope, breadth, and impact of our work. Our proposed studies will reveal the mechanisms of two evolutionarily ancient and important machines, which will not only impact the fields of DNA replication/repair and virus assembly but also atpase biology in general. There are numerous diseases associated with dysregulation of sliding clamps and clamp loaders, and terminases are the target of FDA-approved drugs against viral pathogens. Therefore, our studies have the potential to impact human health. More broadly, our studies lay the groundwork for engineering atpase nanomachines with novel activities or modes of regulation.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $82,675 | |
| Amendment | $66,928 | |
| Amendment | $66,928 | |
| Amendment | $602,353 | |
| Amendment | $602,353 | |
| Amendment | $602,353 | |
| Original award | $669,281 |
Quick answers
Who received award R35GM156361?
R35GM156361 was awarded to University Of Massachusetts Medical School by National Institute of General Medical Sciences (National Institutes of Health) on January 1, 2025.
How much is award R35GM156361 worth?
$2,692,871 has been obligated on R35GM156361.
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