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Crystal packing analysis of murine VDAC1 crystals in a lipidic environment reveals novel insights on oligomerization and orientation.

ABSTRACT: All eukaryotic cells require efficient trafficking of metabolites between the mitochondria and the rest of the cell. This exchange is carried out by the dominant protein in the outer mitochondrial membrane (OMM), the Voltage Dependent Anion Channel (VDAC), which serves as the primary pathway for the exchange of ions and metabolites between the cytoplasm and the intermembrane space of the mitochondria. Additionally, VDAC provides a scaffold for the binding of modulator proteins to the mitochondria and has been implicated in mitochondria-dependent cell death. We recently determined the structure of the murine VDAC1 (mVDAC1) at 2.3 A resolution crystallized in a native-like bilayer environment. The high-resolution structure provided concise structural details about the voltage-sensing N-terminal domain and catalyzed new hypotheses regarding the gating mechanisms for metabolites and ions that transit the OMM. In this study, the crystal packing of mVDAC1 is analyzed revealing a strong antiparallel dimer that further assemble as hexamers mimicking the native oligomeric packing observed in EM and AFM images of the OMM. Oligomerization has been shown to be important for VDAC regulation and function, and mVDAC1 crystal packing in a lipidic medium reveals insights on how oligomerization is accomplished using protein-protein and protein-lipid interactions. Furthermore, orientation of VDAC in the OMM remains uncertain due to inconsistencies in antibody labeling studies. The physiological implications of a novel antiparallel arrangement are addressed that may clarify these conflicting biochemical data.

SUBMITTER: Ujwal R

PROVIDER: S-EPMC3719987 | biostudies-literature | 2009 May-Jun

REPOSITORIES: biostudies-literature

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Crystal packing analysis of murine VDAC1 crystals in a lipidic environment reveals novel insights on oligomerization and orientation.

Ujwal Rachna R Cascio Duilio D Chaptal Vincent V Ping Peipei P Abramson Jeff J

Channels (Austin, Tex.) 20090515 3

All eukaryotic cells require efficient trafficking of metabolites between the mitochondria and the rest of the cell. This exchange is carried out by the dominant protein in the outer mitochondrial membrane (OMM), the Voltage Dependent Anion Channel (VDAC), which serves as the primary pathway for the exchange of ions and metabolites between the cytoplasm and the intermembrane space of the mitochondria. Additionally, VDAC provides a scaffold for the binding of modulator proteins to the mitochondri ...[more]

PMID: 19574737

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Project description:BACKGROUND:Plasmodium falciparum is the protozoan parasite primarily responsible for more than one million malarial deaths, annually, and is developing resistance to current therapies. Throughout its lifespan, the parasite is subjected to oxidative attack, so Plasmodium antioxidant defences are essential for its survival and are targets for disease control. RESULTS:To further understand the molecular aspects of the Plasmodium redox system, we solved 4 structures of Plasmodium peroxiredoxins (Prx). Our study has confirmed PvTrx-Px1 to be a hydrogen peroxide (H2O2)-sensitive peroxiredoxin. We have identified and characterized the novel toroid octameric oligomer of PyTrx-Px1, which may be attributed to the interplay of several factors including: (1) the orientation of the conserved surface/buried arginine of the NNLA(I/L)GRS-loop; and (2) the C-terminal tail positioning (also associated with the aforementioned conserved loop) which facilitates the intermolecular hydrogen bond between dimers (in an A-C fashion). In addition, a notable feature of the disulfide bonds in some of the Prx crystal structures is discussed. Finally, insight into the latter stages of the peroxiredoxin reaction coordinate is gained. Our structure of PyPrx6 is not only in the sulfinic acid (RSO2H) form, but it is also with glycerol bound in a way (not previously observed) indicative of product binding. CONCLUSIONS:The structural characterization of Plasmodium peroxiredoxins provided herein provides insight into their oligomerization and product binding which may facilitate the targeting of these antioxidant defences. Although the structural basis for the octameric oligomerization is further understood, the results yield more questions about the biological implications of the peroxiredoxin oligomerization, as multiple toroid configurations are now known. The crystal structure depicting the product bound active site gives insight into the overoxidation of the active site and allows further characterization of the leaving group chemistry.

Dataset Information

Crystal packing analysis of murine VDAC1 crystals in a lipidic environment reveals novel insights on oligomerization and orientation.

Publications

Crystal packing analysis of murine VDAC1 crystals in a lipidic environment reveals novel insights on oligomerization and orientation.

Similar Datasets

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