Evidence Supporting the 19 β-Strand Model for Tom40 from Cysteine Scanning and Protease Site Accessibility Studies

Lackey, Sebastian W.K.; Taylor, Rebecca D.; Go, Nancy E.; Wong, Amy; Sherman, E. L.; Nargang, Frank E.

doi:10.1074/jbc.m114.578765

Cited by 16 publications

(8 citation statements)

References 56 publications

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“…Due to the close evolutionary relationship between VDAC and Tom40, data from both proteins taken together have enhanced the understanding of the VDAC structure. In-organello , cysteine and protease-accessibility mapping studies of Tom40 in the MOM clearly supported the 19-stranded VDAC model (Lackey et al, 2014 ) (see Figure 3C ). More recently, cryo-electron microscopy (EM) of isolated and dimeric Tom40 complexes from N. crassa provided additional evidence for the accuracy of the 19-stranded VDAC structure, since it was used to construct the Tom40 model (Bausewein et al, 2017 ).…”

Section: Structural and Functional Studies On Vdac And Tom40 Confirm supporting

confidence: 70%

Ten Years of High Resolution Structural Research on the Voltage Dependent Anion Channel (VDAC)—Recent Developments and Future Directions

Zeth

Zachariae

2018

Front. Physiol.

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Mitochondria are evolutionarily related to Gram-negative bacteria and both comprise two membrane systems with strongly differing protein composition. The major protein in the outer membrane of mitochondria is the voltage-dependent anion channel (VDAC), which mediates signal transmission across the outer membrane but also the exchange of metabolites, most importantly ADP and ATP. More than 30 years after its discovery three identical high-resolution structures were determined in 2008. These structures show a 19-stranded anti-parallel beta-barrel with an N-terminal helix located inside. An odd number of beta-strands is also shared by Tom40, another member of the VDAC superfamily. This indicates that this superfamily is evolutionarily relatively young and that it has emerged in the context of mitochondrial evolution. New structural information obtained during the last decade on Tom40 can be used to cross-validate the structure of VDAC and vice versa. Interpretation of biochemical and biophysical studies on both protein channels now rests on a solid basis of structural data. Over the past 10 years, complementary structural and functional information on proteins of the VDAC superfamily has been collected from in-organello, in-vitro, and in silico studies. Most of these findings have confirmed the validity of the original structures. This short article briefly reviews the most important advances on the structure and function of VDAC superfamily members collected during the last decade and summarizes how they enhanced our understanding of the channel.

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Section: Structural and Functional Studies On Vdac And Tom40 Confirm supporting

confidence: 70%

Ten Years of High Resolution Structural Research on the Voltage Dependent Anion Channel (VDAC)—Recent Developments and Future Directions

Zeth

Zachariae

2018

Front. Physiol.

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“…The translocation pore through which precursor polypeptides must pass is formed by Tom40 (ref. 5,[11][12][13], a β-barrel protein structurally related to the voltage-dependent anion-selective channel VDAC, a major mitochondrial porin 14,15 . The other Tom proteins are associated with Tom40 by their single α-helical transmembrane segments (TMs).…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM structure of the mitochondrial protein-import channel TOM complex at near-atomic resolution

Tucker

Park

2019

Nat Struct Mol Biol

151

161

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Nearly all mitochondrial proteins are encoded by the nuclear genome and imported into mitochondria following synthesis on cytosolic ribosomes. These precursor proteins are translocated into mitochondria by the TOM complex, a protein-conducting channel in the mitochondrial outer membrane. We have determined high-resolution cryo-EM structures of the core TOM complex from Saccharomyces cerevisiae in dimeric and tetrameric forms. Dimeric TOM consists of two copies each of five proteins arranged in twofold symmetry, pore-forming β-barrel protein Tom40 and four auxiliary α-helical transmembrane proteins. The pore of each Tom40 has an overall negatively charged inner surface attributed to multiple functionally important acidic patches. The tetrameric complex is essentially a dimer of dimeric TOM, which may be capable of forming higher-order oligomers. Our study reveals the detailed molecular organization of the TOM complex and provides new insights about the mechanism of protein translocation into mitochondria.

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“…The latter position and orientation of the helix has been corroborated in a solid-state NMR study [ 7 ]. Although the biological significance of these 3D structures has been debated because of divergences with previously proposed empirical models [ 8 , 9 ], an increasing number of recent reports support their physiological relevance [ 10 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

Dual Mechanism of Ion Permeation through VDAC Revealed with Inorganic Phosphate Ions and Phosphate Metabolites

Krammer

Homblé

et al. 2015

PLoS ONE

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In the exchange of metabolites and ions between the mitochondrion and the cytosol, the voltage-dependent anion channel (VDAC) is a key element, as it forms the major transport pathway for these compounds through the mitochondrial outer membrane. Numerous experimental studies have promoted the idea that VDAC acts as a regulator of essential mitochondrial functions. In this study, using a combination of molecular dynamics simulations, free-energy calculations, and electrophysiological measurements, we investigated the transport of ions through VDAC, with a focus on phosphate ions and metabolites. We showed that selectivity of VDAC towards small anions including monovalent phosphates arises from short-lived interactions with positively charged residues scattered throughout the pore. In dramatic contrast, permeation of divalent phosphate ions and phosphate metabolites (AMP and ATP) involves binding sites along a specific translocation pathway. This permeation mechanism offers an explanation for the decrease in VDAC conductance measured in the presence of ATP or AMP at physiological salt concentration. The binding sites occur at similar locations for the divalent phosphate ions, AMP and ATP, and contain identical basic residues. ATP features a marked affinity for a central region of the pore lined by two lysines and one arginine of the N-terminal helix. This cluster of residues together with a few other basic amino acids forms a “charged brush” which facilitates the passage of the anionic metabolites through the pore. All of this reveals that VDAC controls the transport of the inorganic phosphates and phosphate metabolites studied here through two different mechanisms.

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Evidence Supporting the 19 β-Strand Model for Tom40 from Cysteine Scanning and Protease Site Accessibility Studies

Cited by 16 publications

References 56 publications

Ten Years of High Resolution Structural Research on the Voltage Dependent Anion Channel (VDAC)—Recent Developments and Future Directions

Ten Years of High Resolution Structural Research on the Voltage Dependent Anion Channel (VDAC)—Recent Developments and Future Directions

Cryo-EM structure of the mitochondrial protein-import channel TOM complex at near-atomic resolution

Dual Mechanism of Ion Permeation through VDAC Revealed with Inorganic Phosphate Ions and Phosphate Metabolites

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