Mitochondrial AAA proteases: A stairway to degradation

Steele, Tyler E.; Glynn, Steven E.

doi:10.1016/j.mito.2019.07.012

Cited by 16 publications

(9 citation statements)

References 92 publications

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“…The fitted 4WW0 subunits suggest the presence of a central orifice in the proteolytic domain, but the cryo-EM structure lacks it, likely owing to insufficient resolution and the introduction of the sixfold symmetry. On the other hand, the fitted ATPase domains form an ∼20-Å ring entrance into the proteolytic chamber, in agreement to structures of other proteases ( 20 , 27 , 28 , 29 ). Adjacent to the first residue of the fitted crystal structures, M141, a narrow density extends from the cytosolic domain toward the inner part of the N-terminal domain and joins an inner ring of ∼40 Å outer diameter and ∼18 Å inner diameter, which is formed by all six N termini ( Fig.…”

Section: Resultssupporting

confidence: 86%

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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Section: Resultssupporting

confidence: 86%

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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“…Exceptions include Afg312, a human mitochondrial FtsH, that can form both homocomplexes and heterocomplexes with paraplegin ( Casari et al, 1998 ; Karlberg et al, 2009 ; Gerdes et al, 2012 ; Patron et al, 2018 ) and FtsH3 and FtsH10 in Arabidopsis mitochondria which form both homo- and heterocomplexes ( Piechota et al, 2010 ). A variety of experimental data suggest that FtsH heterocomplexes in diverse organisms contain two types of FtsH protomer in a 1:1 stoichiometry ( Lee et al, 2011 ; Boehm et al, 2012 ; Langklotz et al, 2012 ; Kato and Sakamoto, 2018 ; Steele and Glynn, 2019 ). However, possible exceptions are some type A/type B FtsH heterocomplexes isolated from Arabidopsis which have been suggested to contain the two forms in a 1:2 ratio ( Moldavski et al, 2012 ) although a recent study supports a 1:1 ratio ( Kato et al, 2018 ).…”

Section: The Basics Of Ftsh Proteasesmentioning

confidence: 99%

“…FtsH proteases are safeguards of photosynthesis and respiration and are found in the thylakoid and the mitochondrial inner membranes, where the major photosynthetic and respiratory electron transport machineries are located. Both photosynthesis and respiration are subject to oxidative stress, hence the proteins involved are often short-lived due to damage by reactive oxygen species (ROS) ( Krynická et al, 2014 ; Steele and Glynn, 2019 ). Spatially coordinated FtsH complexes can efficiently recognize and remove damaged proteins, thus leave room for de novo produced replacements to be incorporated to reactivate the pathway ( Janska et al, 2010 ; Nixon et al, 2010 ; Kato and Sakamoto, 2018 ).…”

Section: The Basics Of Ftsh Proteasesmentioning

confidence: 99%

“…FtsH proteases are found on both sides of the mitochondrial inner membrane, namely m -AAA and i -AAA, originally identified in studies on yeast ( Thorsness et al, 1993 ; Guelin et al, 1994 ; Tzagoloff et al, 1994 ; Leonhard et al, 1996 ). The soluble domains of m -AAA are exposed to the inner matrix, whereas that of i- AAA face the intermembrane space ( Figure 4 ; Leonhard et al, 1996 ; Steele and Glynn, 2019 ). Mitochondrial FtsH complexes target diverse substrates and exhibit functional overlap with other proteases.…”

Section: Respiration and Ftshmentioning

confidence: 99%

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Recent Advances in Understanding the Structural and Functional Evolution of FtsH Proteases

Liu

Nixon

et al. 2022

Front. Plant Sci.

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The FtsH family of proteases are membrane-anchored, ATP-dependent, zinc metalloproteases. They are universally present in prokaryotes and the mitochondria and chloroplasts of eukaryotic cells. Most bacteria bear a single ftsH gene that produces hexameric homocomplexes with diverse house-keeping roles. However, in mitochondria, chloroplasts and cyanobacteria, multiple FtsH homologs form homo- and heterocomplexes with specialized functions in maintaining photosynthesis and respiration. The diversification of FtsH homologs combined with selective pairing of FtsH isomers is a versatile strategy to enable functional adaptation. In this article we summarize recent progress in understanding the evolution, structure and function of FtsH proteases with a focus on the role of FtsH in photosynthesis and respiration.

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“…A pivotal role in mitochondrial protein quality control, is played by members of the AAA+ ( A TPases A ssociated with diverse cellular A ctivities) protein family, that perform ATP-driven unfolding, extraction and degradation of damaged and dysfunctional proteins ( Gates and Martin 2020 ; Song et al. 2021 ; Steele and Glynn 2019 ). The AAA+ proteins are hetero- or homo-oligomeric complexes, that assemble to form ring-like structures ( Gerdes et al.…”

Section: Introductionmentioning

confidence: 99%

Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery

Sharma

Osman

2022

Biological Chemistry

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The mitochondrial respiratory chain is composed of nuclear as well as mitochondrial-encoded subunits. A variety of factors mediate co-translational integration of mtDNA-encoded proteins into the inner membrane. In Saccharomyces cerevisiae, Mdm38 and Mba1 are ribosome acceptors that recruit the mitochondrial ribosome to the inner membrane, where the insertase Oxa1, facilitates membrane integration of client proteins. The protein Yme2 has previously been shown to be localized in the inner mitochondrial membrane and has been implicated in mitochondrial protein biogenesis, but its mode of action remains unclear. Here, we show that multiple copies of Yme2 assemble into a high molecular weight complex. Using a combination of bioinformatics and mutational analyses, we find that Yme2 possesses an RNA recognition motif (RRM), which faces the mitochondrial matrix and a AAA+ domain that is located in the intermembrane space. We further show that YME2 genetically interacts with MDM38, MBA1 and OXA1, which links the function of Yme2 to the mitochondrial protein biogenesis machinery.

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Mitochondrial AAA proteases: A stairway to degradation

Cited by 16 publications

References 92 publications

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

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

Recent Advances in Understanding the Structural and Functional Evolution of FtsH Proteases

Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery

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