Unknown

Dataset Information

0

Networks of Dynamic Allostery Regulate Enzyme Function.


ABSTRACT: Many protein systems rely on coupled dynamic networks to allosterically regulate function. However, the broad conformational space sampled by non-coherently dynamic systems has precluded detailed analysis of their communication mechanisms. Here, we have developed a methodology that combines the high sensitivity afforded by nuclear magnetic resonance relaxation techniques and single-site multiple mutations, termed RASSMM, to identify two allosterically coupled dynamic networks within the non-coherently dynamic enzyme cyclophilin A. Using this methodology, we discovered two key hotspot residues, Val6 and Val29, that communicate through these networks, the mutation of which altered active-site dynamics, modulating enzymatic turnover of multiple substrates. Finally, we utilized molecular dynamics simulations to identify the mechanism by which one of these hotspots is coupled to the larger dynamic networks. These studies confirm a link between enzyme dynamics and the catalytic cycle of cyclophilin A and demonstrate how dynamic allostery may be engineered to tune enzyme function.

SUBMITTER: Holliday MJ 

PROVIDER: S-EPMC5336394 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

Networks of Dynamic Allostery Regulate Enzyme Function.

Holliday Michael Joseph MJ   Camilloni Carlo C   Armstrong Geoffrey Stuart GS   Vendruscolo Michele M   Eisenmesser Elan Zohar EZ  

Structure (London, England : 1993) 20170112 2


Many protein systems rely on coupled dynamic networks to allosterically regulate function. However, the broad conformational space sampled by non-coherently dynamic systems has precluded detailed analysis of their communication mechanisms. Here, we have developed a methodology that combines the high sensitivity afforded by nuclear magnetic resonance relaxation techniques and single-site multiple mutations, termed RASSMM, to identify two allosterically coupled dynamic networks within the non-cohe  ...[more]

Similar Datasets

| S-EPMC8173106 | biostudies-literature
| S-EPMC4786136 | biostudies-literature
| S-EPMC4610412 | biostudies-literature
| S-EPMC2529343 | biostudies-literature
| S-EPMC7467759 | biostudies-literature
| S-EPMC5347623 | biostudies-literature
| S-EPMC7370311 | biostudies-literature
| S-EPMC2962503 | biostudies-literature
| S-EPMC4664340 | biostudies-literature
| S-EPMC6033628 | biostudies-literature