Structural studies on<i>Helicobacter pylori</i>ATP-dependent protease, FtsH

Kim, Sung Hyun; Kang, Gil Bu; Song, Hajun; Park, Soo‐Jin; Bea, Man Ho; Eom, Soo Hyun

doi:10.1107/s090904950706846x

Cited by 5 publications

(4 citation statements)

References 7 publications

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“…Further analysis of this compartment may shed light on the mechanisms of trafficking of membrane proteins to the apicoplast. Interestingly, although both of these tag insertions are C-terminal to the TMD, the crystal structure of bacterial FtsHs [39–41] predicts they are far apart in the folded protein. Hence changes in disparate regions of the FtsH1 can affect the steady state localization of the protein after it enters the ER.…”

Section: Discussionmentioning

confidence: 99%

Sequential processing of the Toxoplasma apicoplast membrane protein FtsH1 in topologically distinct domains during intracellular trafficking

Karnataki

DeRocher

Feagin

et al. 2009

Molecular and Biochemical Parasitology

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FtsH proteins are hexameric transmembrane proteases found in chloroplasts, mitochondria and bacteria. In the protozoan Toxoplasma gondii, FtsH1 is localized to membranes of the apicoplast, a relict chloroplast present in many apicomplexan parasites. We have shown that although T. gondii FtsH1 lacks the typical bipartite targeting presequence seen on apicoplast luminal proteins, it is targeted to the apicoplast via the endoplasmic reticulum. In this report, we show that FtsH1 undergoes processing events to remove both the N-and C-termini, which are topologically separated by the membrane in which FtsH1 is embedded. Pulse-chase analysis showed that N-terminal cleavage precedes C-terminal cleavage. Unlike the processing of the N-terminal transit peptide of luminal proteins, which occurs in the apicoplast, analysis of ER-retained mutants showed that N-terminal processing of FtsH1 occurs in the endoplasmic reticulum. Two of four FtsH1 mutants bearing internal epitope tags accumulated in structures peripheral to the apicoplast, implying that FtsH1 trafficking is highly sensitive to changes in protein structure. These mutant proteins did not undergo C-terminal processing, suggesting that this processing step occurs after localization to the plastid. Mutation of the peptidase active site demonstrated that neither processing event occurrs in cis. These data support a model in which multiple proteases act at different points of the trafficking pathway to form mature FtsH1, making its processing more complex than other FtsHs and unique among apicoplast proteins described thus far.

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Section: Discussionmentioning

confidence: 99%

Sequential processing of the Toxoplasma apicoplast membrane protein FtsH1 in topologically distinct domains during intracellular trafficking

Karnataki

DeRocher

Feagin

et al. 2009

Molecular and Biochemical Parasitology

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“…First pieces of three-dimensional structural information emerged from crystal structure analyses of isolated AAA domains [8,9]. More recently, two further crystal structures of isolated FtsH AAA domains from Helicobacter pylori and human paraplegin have been published [10,11]. All those single AAA domains are monomeric and void of ATPase activity.…”

Section: Tertiary Structurementioning

confidence: 99%

Structure and function of the bacterial AAA protease FtsH

Langklotz

Baumann

Narberhaus

2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

170

150

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Proteolysis of regulatory proteins or key enzymes of biosynthetic pathways is a universal mechanism to rapidly adjust the cellular proteome to particular environmental needs. Among the five energy-dependent AAA(+) proteases in Escherichia coli, FtsH is the only essential protease. Moreover, FtsH is unique owing to its anchoring to the inner membrane. This review describes the structural and functional properties of FtsH. With regard to its role in cellular quality control and regulatory circuits, cytoplasmic and membrane substrates of the FtsH protease are depicted and mechanisms of FtsH-dependent proteolysis are discussed.

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“…Structural studies have used truncated FtsH forms with only the soluble C-terminal (cytosolic) part ( 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ) or with only the periplasmic domain ( 12 ). The single full-length structure known concerns m -AAA, the yeast mitochondrial ortholog of bacterial FtsH, which has been resolved at 12 Å resolution by cryo-electron microscopy (cryo-EM) ( 21 ).…”

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confidence: 99%

The cytoplasmic domain of the AAA+ protease FtsH is tilted with respect to the membrane to facilitate substrate entry

Carvalho

Prabudiansyah

Kováčik

et al. 2021

Journal of Biological Chemistry

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AAA+ proteases are degradation machines that use ATP hydrolysis to unfold protein substrates and translocate them through a central pore towards a degradation chamber. FtsH, a bacterial membrane-anchored AAA+ protease, plays a vital role in membrane protein quality control. How substrates reach the FtsH central pore is an open key question that is not resolved by the available atomic structures of cytoplasmic and periplasmic domains. In this work, we used both negative stain TEM and cryo-EM to determine 3D maps of the full-length Aquifex aeolicus FtsH protease. Unexpectedly, we observed that detergent solubilisation induces the formation of fully active FtsH dodecamers, which consist of two FtsH hexamers in a single detergent micelle. The striking tilted conformation of the cytosolic domain in the FtsH dodecamer visualized by negative stain TEM suggests a lateral substrate entrance between membrane and cytosolic domain. Such a substrate path was then resolved in the cryo-EM structure of the FtsH hexamer. By mapping the available structural information and structure predictions for the transmembrane helices to the amino acid sequence we identified a linker of ~20 residues between the second transmembrane helix and the cytosolic domain. This unique polypeptide appears to be highly flexible, and turned out to be essential for proper functioning of FtsH as its deletion fully eliminated the proteolytic activity of FtsH.

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Structural studies onHelicobacter pyloriATP-dependent protease, FtsH

Cited by 5 publications

References 7 publications

Sequential processing of the Toxoplasma apicoplast membrane protein FtsH1 in topologically distinct domains during intracellular trafficking

Sequential processing of the Toxoplasma apicoplast membrane protein FtsH1 in topologically distinct domains during intracellular trafficking

Structure and function of the bacterial AAA protease FtsH

The cytoplasmic domain of the AAA+ protease FtsH is tilted with respect to the membrane to facilitate substrate entry

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