Dataset Information

Transconformations of the SERCA1 Ca-ATPase: a normal mode study.

ABSTRACT: The transport of Ca(2+) by Ca-ATPase across the sarcoplasmic reticulum membrane is accompanied by several transconformations of the protein. Relying on the already established functional importance of low-frequency modes in dynamics of proteins, we report here a normal mode analysis of the Ca(2+)-ATPase based on the crystallographic structures of the E1Ca(2) and E2TG forms. The lowest-frequency modes reveal that the N and A(+Nter) domains undergo the largest amplitude movements. The dynamical domain analysis performed with the DomainFinder program suggests that they behave as rigid bodies, unlike the highly flexible P domain. We highlight two types of movements of the transmembrane helices: i), a concerted movement around an axis perpendicular to the membrane which "twists open" the lumenal side of the protein and ii), an individual translational and rotational mobility which is of lower amplitude for the helices hosting the calcium binding sites. Among all modes calculated for E1Ca, only three are enough to describe the transition to E2TG; the associated movements involve almost exclusively the A and N domains, reflecting the closure of the cytoplasmic headpiece and high displacement of the L7-8 lumenal loop. Subsequently, we discuss the potential contribution of the remaining low-frequency normal modes to the transconformations occurring within the overall calcium transport cycle.

SUBMITTER: Reuter N

PROVIDER: S-EPMC1303445 | biostudies-literature | 2003 Oct

REPOSITORIES: biostudies-literature

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Transconformations of the SERCA1 Ca-ATPase: a normal mode study.

Reuter Nathalie N Hinsen Konrad K Lacapère Jean-Jacques JJ

Biophysical journal 20031001 4

The transport of Ca(2+) by Ca-ATPase across the sarcoplasmic reticulum membrane is accompanied by several transconformations of the protein. Relying on the already established functional importance of low-frequency modes in dynamics of proteins, we report here a normal mode analysis of the Ca(2+)-ATPase based on the crystallographic structures of the E1Ca(2) and E2TG forms. The lowest-frequency modes reveal that the N and A(+Nter) domains undergo the largest amplitude movements. The dynamical do ...[more]

PMID: 14507684

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Project description:The structural flexibilities of two molecular machines, myosin and Ca(2+)-ATPase, have been analyzed with normal mode analysis and discussed in the context of their energy conversion functions. The normal mode analysis with physical intermolecular interactions was made possible by an improved implementation of the block normal mode (BNM) approach. The BNM results clearly illustrated that the large-scale conformational transitions implicated in the functional cycles of the two motor systems can be largely captured with a small number of low-frequency normal modes. Therefore, the results support the idea that structural flexibility is an essential part of the construction principle of molecular motors through evolution. Such a feature is expected to be more prevalent in motor proteins than in simpler systems (e.g., signal transduction proteins) because in the former, large-scale conformational transitions often have to occur before the chemical events (e.g., ATP hydrolysis in myosin and ATP binding/phosphorylation in Ca(2+)-ATPase). This highlights the importance of Brownian motions associated with the protein domains that are involved in the functional transitions; in this sense, Brownian molecular machines is an appropriate description of molecular motors, although the normal mode results do not address the origin of the ratchet effect. The results also suggest that it might be more appropriate to describe functional transitions in some molecular motors as intrinsic elastic motions modulating local structural changes in the active site, which in turn gets stabilized by the subsequent chemical events, in contrast with the conventional idea of local changes somehow getting amplified into larger-scale motions. In the case of myosin, for example, we favor the idea that Brownian motions associated with the flexible converter propagates to the Switch I/II region, where the salt-bridge formation gets stabilized by ATP hydrolysis, in contrast with the textbook notion that ATP hydrolysis drives the converter motion. Another useful aspect of the BNM results is that selected low-frequency normal modes have been identified to form a set of collective coordinates that can be used to characterize the progress of a significant fraction of large-scale conformational transitions. Therefore, the present normal mode analysis has provided a stepping-stone toward more elaborate microscopic simulations for addressing critical issues in free energy conversions in molecular machines, such as the coupling and the causal relationship between collective motions and essential local changes at the catalytic active site where ATP hydrolysis occurs.

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Transconformations of the SERCA1 Ca-ATPase: a normal mode study.

Publications

Transconformations of the SERCA1 Ca-ATPase: a normal mode study.

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