Dataset Information

Apparent tradeoff of higher activity in MMP-12 for enhanced stability and flexibility in MMP-3.

ABSTRACT: The greater activity of MMP-12 than MMP-3 toward substrates from protein fibrils has been quantified. Why is MMP-12 the more active protease? We looked for behaviors associated with the higher activity of MMP-12 than MMP-3, using nuclear magnetic resonance to monitor backbone dynamics and residue-specific stabilities of their catalytic domain. The proteolytic activities are likely to play important roles in inflammatory diseases of arteries, lungs, joints, and intestines. Nuclear magnetic resonance line broadening indicates that regions surrounding the active sites of both proteases sample conformational substates within milliseconds. The more extensive line broadening in MMP-3 suggests greater sampling of conformational substates, affecting the full length of helix B and beta-strand IV forming the active site, and more remote sites. This could suggest more excursions to functionally incompetent substates. MMP-3 also has enhanced subnanosecond fluctuations in helix A, in the beta-hairpin of strands IV and V, and before and including helix C. Hydrogen exchange protection in the EX2 regime suggests that MMP-3 possesses 2.8 kcal/mol higher folding stability than MMP-12(E219A). The beta-sheet of MMP-3 appears to be stabilized still more. The higher stability of MMP-3 relative to MMP-12 coincides with the former's considerably lower proteolytic activity. This relationship is consistent with the hypothesis that enzymes often trade stability for higher activity.

SUBMITTER: Liang X

PROVIDER: S-EPMC2895380 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Apparent tradeoff of higher activity in MMP-12 for enhanced stability and flexibility in MMP-3.

Liang Xiangyang X Arunima A A Zhao Yingchu Y Bhaskaran Rajagopalan R Shende Anuradha A Byrne Todd S TS Fleeks Jeremy J Palmier Mark O MO Van Doren Steven R SR

Biophysical journal 20100701 1

The greater activity of MMP-12 than MMP-3 toward substrates from protein fibrils has been quantified. Why is MMP-12 the more active protease? We looked for behaviors associated with the higher activity of MMP-12 than MMP-3, using nuclear magnetic resonance to monitor backbone dynamics and residue-specific stabilities of their catalytic domain. The proteolytic activities are likely to play important roles in inflammatory diseases of arteries, lungs, joints, and intestines. Nuclear magnetic resona ...[more]

PMID: 20655856

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Project description:Uncovering the underlying biophysical principles of emergent collective computational abilities, such as working memory, in neural circuits is one of the most essential concerns in modern neuroscience. Working memory system is often desired to be robust against noises. Such systems can be highly flexible for adapting environmental demands. How neural circuits reconfigure themselves according to the cognitive task requirement remains unclear. Previous studies explored the robustness and the flexibility in working memory by tracing individual dynamical trajectories in a limited time scale, where the accuracy of the results depends on the volume of the collected statistical data. Inspired by thermodynamics and statistical mechanics in physical systems, we developed a non-equilibrium landscape and flux framework for studying the neural network dynamics. Applying this approach to a biophysically based working memory model, we investigated how changes in the recurrent excitation mediated by slow NMDA receptors within a selective population and mutual inhibition mediated by GABAergic interneurons between populations affect the robustness against noises. This is realized through quantifying the underlying non-equilibrium potential landscape topography and the kinetics of state switching. We found that an optimal compromise for a working memory circuit between the robustness and the flexibility can be achieved through the emergence of an intermediate state between the working memory states. An optimal combination of both increased self-excitation and inhibition can enhance the flexibility to external signals without significantly reducing the robustness to the random fluctuations. Furthermore, we found that the enhanced performance in working memory is supported by larger energy consumption. Our approach can facilitate the design of new network structure for cognitive functions with the optimal balance between performance and cost. Our work also provides a new paradigm for exploring the underlying mechanisms of many cognitive functions based on non-equilibrium physics.

Dataset Information

Apparent tradeoff of higher activity in MMP-12 for enhanced stability and flexibility in MMP-3.

Publications

Apparent tradeoff of higher activity in MMP-12 for enhanced stability and flexibility in MMP-3.

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