The dynamical mechanism of auto-inhibition of AMP-activated protein kinase.
We use a novel normal mode analysis of an elastic network model drawn from configurations generated during microsecond all-atom molecular dynamics simulations to analyze the mechanism of auto-inhibition of AMP-activated protein kinase (AMPK). A recent X-ray and mutagenesis experiment (Chen, et al Na...
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Public Library of Science (PLoS)
2011-07-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1002082&type=printable |
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| author | Cheng Peng Teresa Head-Gordon |
| author_facet | Cheng Peng Teresa Head-Gordon |
| author_sort | Cheng Peng |
| collection | DOAJ |
| description | We use a novel normal mode analysis of an elastic network model drawn from configurations generated during microsecond all-atom molecular dynamics simulations to analyze the mechanism of auto-inhibition of AMP-activated protein kinase (AMPK). A recent X-ray and mutagenesis experiment (Chen, et al Nature 2009, 459, 1146) of the AMPK homolog S. Pombe sucrose non-fermenting 1 (SNF1) has proposed a new conformational switch model involving the movement of the kinase domain (KD) between an inactive unphosphorylated open state and an active or semi-active phosphorylated closed state, mediated by the autoinhibitory domain (AID), and a similar mutagenesis study showed that rat AMPK has the same auto-inhibition mechanism. However, there is no direct dynamical evidence to support this model and it is not clear whether other functionally important local structural components are equally inhibited. By using the same SNF1 KD-AID fragment as that used in experiment, we show that AID inhibits the catalytic function by restraining the KD into an unproductive open conformation, thereby limiting local structural rearrangements, while mutations that disrupt the interactions between the KD and AID allow for both the local structural rearrangement and global interlobe conformational transition. Our calculations further show that the AID also greatly impacts the structuring and mobility of the activation loop. |
| format | Article |
| id | doaj-art-1a874b0ad0364f87908056c9dc6e7fc6 |
| institution | OA Journals |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2011-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-1a874b0ad0364f87908056c9dc6e7fc62025-08-20T02:15:30ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582011-07-0177e100208210.1371/journal.pcbi.1002082The dynamical mechanism of auto-inhibition of AMP-activated protein kinase.Cheng PengTeresa Head-GordonWe use a novel normal mode analysis of an elastic network model drawn from configurations generated during microsecond all-atom molecular dynamics simulations to analyze the mechanism of auto-inhibition of AMP-activated protein kinase (AMPK). A recent X-ray and mutagenesis experiment (Chen, et al Nature 2009, 459, 1146) of the AMPK homolog S. Pombe sucrose non-fermenting 1 (SNF1) has proposed a new conformational switch model involving the movement of the kinase domain (KD) between an inactive unphosphorylated open state and an active or semi-active phosphorylated closed state, mediated by the autoinhibitory domain (AID), and a similar mutagenesis study showed that rat AMPK has the same auto-inhibition mechanism. However, there is no direct dynamical evidence to support this model and it is not clear whether other functionally important local structural components are equally inhibited. By using the same SNF1 KD-AID fragment as that used in experiment, we show that AID inhibits the catalytic function by restraining the KD into an unproductive open conformation, thereby limiting local structural rearrangements, while mutations that disrupt the interactions between the KD and AID allow for both the local structural rearrangement and global interlobe conformational transition. Our calculations further show that the AID also greatly impacts the structuring and mobility of the activation loop.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1002082&type=printable |
| spellingShingle | Cheng Peng Teresa Head-Gordon The dynamical mechanism of auto-inhibition of AMP-activated protein kinase. PLoS Computational Biology |
| title | The dynamical mechanism of auto-inhibition of AMP-activated protein kinase. |
| title_full | The dynamical mechanism of auto-inhibition of AMP-activated protein kinase. |
| title_fullStr | The dynamical mechanism of auto-inhibition of AMP-activated protein kinase. |
| title_full_unstemmed | The dynamical mechanism of auto-inhibition of AMP-activated protein kinase. |
| title_short | The dynamical mechanism of auto-inhibition of AMP-activated protein kinase. |
| title_sort | dynamical mechanism of auto inhibition of amp activated protein kinase |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1002082&type=printable |
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