m‐AAA protease‐driven membrane dislocation allows intramembrane cleavage by rhomboid in mitochondria

doi:10.1038/SJ.EMBOJ.7601514

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m‐AAA protease‐driven membrane dislocation allows intramembrane cleavage by rhomboid in mitochondria

Journal Article•DOI•

m‐AAA protease‐driven membrane dislocation allows intramembrane cleavage by rhomboid in mitochondria

Takashi Tatsuta¹, Steffen Augustin¹, Mark Nolden¹, Björn Friedrichs¹, Thomas Langer¹ - Show less +1 more•Institutions (1)

University of Cologne¹

24 Jan 2007-The EMBO Journal (European Molecular Biology Organization)-Vol. 26, Iss: 2, pp 325-335

TL;DR: Findings reveal for the first time a non‐proteolytic function of the m‐AAA protease during mitochondrial biogenesis and rationalise the requirement of a preceding step for intramembrane cleavage by rhomboid.

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Abstract: Maturation of cytochrome c peroxidase (Ccp1) in mitochondria occurs by the subsequent action of two conserved proteases in the inner membrane: the m-AAA protease, an ATP-dependent protease degrading misfolded proteins and mediating protein processing, and the rhomboid protease Pcp1, an intramembrane cleaving peptidase. Neither the determinants preventing complete proteolysis of certain substrates by the m-AAA protease, nor the obligatory requirement of the m-AAA protease for rhomboid cleavage is currently understood. Here, we describe an intimate and unexpected functional interplay of both proteases. The m-AAA protease mediates the ATP-dependent membrane dislocation of Ccp1 independent of its proteolytic activity. It thereby ensures the correct positioning of Ccp1 within the membrane bilayer allowing intramembrane cleavage by rhomboid. Decreasing the hydrophobicity of the Ccp1 transmembrane segment facilitates its dislocation from the membrane and renders rhomboid cleavage m-AAA protease-independent. These findings reveal for the first time a non-proteolytic function of the m-AAA protease during mitochondrial biogenesis and rationalise the requirement of a preceding step for intramembrane cleavage by rhomboid.

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Book Chapter•DOI•

Biogenesis of Mitochondrial Proteins

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Johannes M. Herrmann, Sebastian Longen, Daniel Weckbecker, Matthieu Depuydt

01 Jan 2012-Advances in Experimental Medicine and Biology

TL;DR: This chapter gives an overview on the mitochondrial protein translocases and the mechanisms by which they drive the transport and assembly of mitochondrial proteins.

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Abstract: Depending on the organism, mitochondria consist approximately of 500–1,400 different proteins. By far most of these proteins are encoded by nuclear genes and synthesized on cytosolic ribosomes. Targeting signals direct these proteins into mitochondria and there to their respective subcompartment: the outer membrane, the intermembrane space (IMS), the inner membrane, and the matrix. Membrane-embedded translocation complexes allow the translocation of proteins across and, in the case of membrane proteins, the insertion into mitochondrial membranes. A small number of proteins are encoded by the mitochondrial genome: Most mitochondrial translation products represent hydrophobic proteins of the inner membrane which—together with many nuclear-encoded proteins—form the respiratory chain complexes. This chapter gives an overview on the mitochondrial protein translocases and the mechanisms by which they drive the transport and assembly of mitochondrial proteins.

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40 citations

Cites background from "m‐AAA protease‐driven membrane disl..."

...Proteins that employ bipartite presequences to reach the IMS are for example cytochrome b 2 (Beasley et al. 1993 ) , cytochrome c peroxidase (Michaelis et al. 2005 ; Tatsuta et al. 2007 ) or Smac/Diablo (Burri et al. 2005 ) ....
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Journal Article•DOI•

Metalloproteases of the Inner Mitochondrial Membrane

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Roman M. Levytskyy¹, Iryna Bohovych¹, Oleh Khalimonchuk¹•Institutions (1)

University of Nebraska–Lincoln¹

30 Aug 2017-Biochemistry

TL;DR: The inner mitochondrial membrane is equipped with a series of highly conserved, proteolytic complexes dedicated to the maintenance of normal protein homeostasis within this mitochondrial subcompartment, and a group of membrane-anchored metallopeptidases commonly known as m-AAA and i-AAA proteases are particularly important.

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Abstract: The inner mitochondrial membrane (IM) is among the most protein-rich cellular compartments. The metastable IM subproteome where the concentration of proteins is approaching oversaturation creates a challenging protein folding environment with a high probability of protein malfunction or aggregation. Failure to maintain protein homeostasis in such a setting can impair the functional integrity of the mitochondria and drive clinical manifestations. The IM is equipped with a series of highly conserved, proteolytic complexes dedicated to the maintenance of normal protein homeostasis within this mitochondrial subcompartment. Particularly important is a group of membrane-anchored metallopeptidases commonly known as m-AAA and i-AAA proteases, and the ATP-independent Oma1 protease. Herein, we will summarize the current biochemical knowledge of these proteolytic machines and discuss recent advances in our understanding of mechanistic aspects of their functioning.

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40 citations

Journal Article•DOI•

The AAA-type ATPases Pex1p and Pex6p and their role in peroxisomal matrix protein import in Saccharomyces cerevisiae.

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Immanuel Grimm¹, Delia Saffian¹, Harald W. Platta², Ralf Erdmann¹•Institutions (2)

Ruhr University Bochum¹, Oslo University Hospital²

01 Jan 2012-Biochimica et Biophysica Acta

TL;DR: The export-driven import model suggests that the AAA-peroxins might function as motor proteins in peroxisomal import by coupling ATP-dependent removal of the peroxISomal import receptor and cargo translocation into the organelle.

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38 citations

Cites background from "m‐AAA protease‐driven membrane disl..."

...Other AAA-complexes are located at the inner membrane of mitochondria (m-AAA-, i-AAA; [17,18]), acting as chaperones (Hsp100 family; [19]), disassemble ESCRT-III complexes (endosomal sorting complex required for transport) at endosomal membranes (Vps4; [20]) or participate in microtubule associated processes as motor proteins (cytoplasmic dynein [21,22]) or severing of these filaments (Fidgetin, Katanin, Spastin; [23–25])....
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Journal Article•DOI•

Autosomal dominant cerebellar ataxias

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Cecilia Marelli, Cécile Cazeneuve, Alexis Brice, Giovanni Stevanin, Alexandra Durr - Show less +1 more

01 May 2011-Revue Neurologique

TL;DR: This review will focus on the genetic features of ADCA and on the clinical differences among the different forms, as well as on the phenomenon of anticipation between generations.

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37 citations

Journal Article•DOI•

The versatility of the mitochondrial presequence processing machinery: cleavage, quality control and turnover

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Daniel Poveda-Huertes¹, Patrycja Mulica¹, F.-Nora Vögtle¹•Institutions (1)

University of Freiburg¹

01 Jan 2017-Cell and Tissue Research

TL;DR: The mitochondrial presequence processing machinery serves the particular purpose of maturing the majority of incoming precursor proteins by presequence cleavage, to ensure a stable mature protein by trimming of intermediate N-termini and to remove free toxic targeting peptides.

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Abstract: Mitochondria play a key role in several metabolic and cell biological pathways and have attracted increasing attention due to their implication in life-span, ageing and human diseases. Mitochondrial proteases have a special role in these multiple biological functions, as they are involved in the regulation of various processes, e.g., mitochondrial protein biogenesis and quality control, mitochondrial dynamics, mitophagy and programmed cell death. The mitochondrial presequence processing machinery serves the particular purpose of maturing the majority of incoming precursor proteins by presequence cleavage, to ensure a stable mature protein by trimming of intermediate N-termini and to remove free toxic targeting peptides.

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37 citations

Cites background from "m‐AAA protease‐driven membrane disl..."

...It positions the polypeptide chain of Ccp1 in the IM in the vicinity of the Pcp1 protease that is then cleaving it within the membrane, which results in the release of mature Ccp1 into the IMS (Tatsuta et al. 2007)....
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...tide chain of Ccp1 in the IM in the vicinity of the Pcp1 protease that is then cleaving it within the membrane, which results in the release of mature Ccp1 into the IMS (Tatsuta et al. 2007)....
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Journal Article•DOI•

AAA+ proteins: have engine, will work.

[...]

Phyllis I. Hanson¹, Sidney W. Whiteheart²•Institutions (2)

Washington University in St. Louis¹, University of Kentucky²

01 Jul 2005-Nature Reviews Molecular Cell Biology

TL;DR: The structural organization of AAA+ proteins, the conformational changes they undergo, the range of different reactions they catalyse, and the diseases associated with their dysfunction are reviewed.

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Abstract: The AAA+ (ATPases associated with various cellular activities) family is a large and functionally diverse group of enzymes that are able to induce conformational changes in a wide range of substrate proteins. The family's defining feature is a structurally conserved ATPase domain that assembles into oligomeric rings and undergoes conformational changes during cycles of nucleotide binding and hydrolysis. Here, we review the structural organization of AAA+ proteins, the conformational changes they undergo, the range of different reactions they catalyse, and the diseases associated with their dysfunction.

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1,137 citations

"m‐AAA protease‐driven membrane disl..." refers background in this paper

...This loop contains an aromatichydrophobic-glycine motif (FVG in Yta10 and Yta12), which is conserved within AAAþ proteins (Figure 7A) and has been linked to substrate translocation in other AAA proteins (Sauer et al, 2004; Hanson and Whiteheart, 2005)....
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...At the same time, they conduct the quality surveillance of cellular proteins and degrade misfolded proteins to peptides (Sauer et al, 2004; Ciechanover, 2005; Hanson and Whiteheart, 2005)....
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...Conserved residues in the pore loop are essential for Ccp1 processing Most AAAþ proteins form hexameric ring structures that allow substrates to enter the central channel (Sauer et al, 2004; Hanson and Whiteheart, 2005)....
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...This loop contains an aromatichydrophobic-glycine motif (FVG in Yta10 and Yta12), which is conserved within AAA proteins (Figure 7A) and has been linked to substrate translocation in other AAA proteins (Sauer et al, 2004; Hanson and Whiteheart, 2005)....
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...Ccp1 processing Most AAA proteins form hexameric ring structures that allow substrates to enter the central channel (Sauer et al, 2004; Hanson and Whiteheart, 2005)....
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Journal Article•DOI•

Proteolysis: from the lysosome to ubiquitin and the proteasome.

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Aaron Ciechanover¹•Institutions (1)

Technion – Israel Institute of Technology¹

01 Jan 2005-Nature Reviews Molecular Cell Biology

TL;DR: In this paper, the ubiquitin-proteasome system resolved the enigma of how cellular proteins are degraded in the lysosome and showed that non-lysosomal pathways have an important role in intracellular proteolysis, although their identity and mechanisms of action remained obscure.

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Abstract: How the genetic code is translated into proteins was a key focus of biological research before the 1980s, but how these proteins are degraded remained a neglected area With the discovery of the lysosome, it was suggested that cellular proteins are degraded in this organelle However, several independent lines of experimental evidence strongly indicated that non-lysosomal pathways have an important role in intracellular proteolysis, although their identity and mechanisms of action remained obscure The discovery of the ubiquitin–proteasome system resolved this enigma

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1,009 citations

Journal Article•DOI•

Regulation of mitochondrial morphology through proteolytic cleavage of OPA1.

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Naotada Ishihara¹, Yuu Fujita¹, Toshihiko Oka¹, Katsuyoshi Mihara¹•Institutions (1)

Kyushu University¹

12 Jul 2006-The EMBO Journal

TL;DR: M mammalian mitochondrial function and morphology is regulated through processing of OPA1 in a ΔΨ‐dependent manner through proteolytic cleavage of Mgm1, the yeast homolog of O PA1.

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Abstract: The dynamin-like GTPase OPA1, a causal gene product of human dominant optic atrophy, functions in mitochondrial fusion and inner membrane remodeling. It has several splice variants and even a single variant is found as several processed forms, although their functional significance is unknown. In yeast, mitochondrial rhomboid protease regulates mitochondrial function and morphology through proteolytic cleavage of Mgm1, the yeast homolog of OPA1. We demonstrate that OPA1 variants are synthesized with a bipartite-type mitochondrial targeting sequence. During import, the matrix-targeting signal is removed and processed forms (L-isoforms) are anchored to the inner membrane in type I topology. L-isoforms undergo further processing in the matrix to produce S-isoforms. Knockdown of OPA1 induced mitochondrial fragmentation, whose network morphology was recovered by expression of L-isoform but not S-isoform, indicating that only L-isoform is fusion-competent. Dissipation of membrane potential, expression of m-AAA protease paraplegin, or induction of apoptosis stimulated this processing along with the mitochondrial fragmentation. Thus, mammalian mitochondrial function and morphology is regulated through processing of OPA1 in a ΔΨ-dependent manner.

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810 citations

"m‐AAA protease‐driven membrane disl..." refers background in this paper

...Of note, proteolytic processing of the Mgm1 homologue OPA1 in mammalian cells has recently been linked to an m-AAA protease (Ishihara et al, 2006)....
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Journal Article•DOI•

Solvation Energies of Amino Acid Side Chains and Backbone in a Family of Host−Guest Pentapeptides

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William C. Wimley¹, Trevor P. Creamer², Stephen H. White²•Institutions (2)

University of California, Irvine¹, Johns Hopkins University School of Medicine²

23 Apr 1996-Biochemistry

TL;DR: The very large peptide bond ASP, -96 +/- 6 cal/mol/A2, profoundly affects the results of computational comparisons of protein stability which use ASPs derived from octanol-water partitioning data.

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Abstract: Octanol-to-water solvation free energies of acetyl amino amides (Ac-X-amides) [Fauchere, J.L., & Pliska, V. (1983) Eur. J. Med. Chem. --Chim. Ther. 18,369] form the basis for computational comparisons of protein stabilities by means of the atomic solvation parameter formalism of Eisenberg and McLachlan [(1986) Nature 319, 199]. In order to explore this approach for more complex systems, we have determined by octanol-to-water partitioning the solvation energies of (1) the guest (X) side chains in the host-guest pentapeptides AcWL-X-LL, (2) the carboxy terminus of the pentapeptides, and (3) the peptide bonds of the homologous series of peptides AcWLm (m = 1-6). Solvation parameters were derived from the solvation energies using estimates of the solvent-accessible surface areas (ASA) obtained from hard-sphere Monte Carlo simulations. The measurements lead to a side chain solvation-energy scale for the pentapeptides and suggest the need for modifying the Asp, Glu, and Cys values of the "Fauchere-Pliska" solvation-energy scale fro the Ac-X-amides. We find that the unfavorable solvation energy of nonpolar residues can be calculated accurately by a solvation parameter of 22.8 +/- 0.8 cal/mol/A2, which agrees satisfactorily with the AC-X-amide data and thereby validates the Monte Carlo ASA results. Unlike the Ac-X-amide data, the apparent solvation energies of the uncharged polar residues are also largely unfavorable. This unexpected finding probably results, primarily, from differences in conformation and hydrogen bonding in octanol and buffer but may also be due to the additional flaking peptide bonds of the pentapeptides. The atomic solvation parameter (ASP) for the peptide bond is comparable to the ASP of the charged carboxy terminus which is an order of magnitude larger than the ASP of the uncharged polar side chains of the Ac-X-amides. The very large peptide bond ASP, -96 +/- 6 cal/mol/A2, profoundly affects the results of computational comparisons of protein stability which use ASPs derived from octanol-water partitioning data.

...read moreread less

538 citations

"m‐AAA protease‐driven membrane disl..." refers methods in this paper

...We determined the hydrophobicity of this region using the membrane protein explorer (MPEx) programme, which is based on experimentally derived Wimley–White hydropathy scale (Wimley et al, 1996)....
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Journal Article•DOI•

Sculpting the Proteome with AAA+ Proteases and Disassembly Machines

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Robert T. Sauer¹, Daniel N. Bolon¹, Briana M. Burton¹, Randall E. Burton¹, Julia M. Flynn¹, Robert A. Grant¹, Greg L. Hersch¹, Shilpa A. Joshi¹, Jon A. Kenniston¹, Igor Levchenko¹, Saskia B. Neher¹, Elizabeth S.C. Oakes¹, Samia M. Siddiqui¹, David A. Wah¹, Tania A. Baker¹ - Show less +11 more•Institutions (1)

Massachusetts Institute of Technology¹

01 Oct 2004-Cell

TL;DR: Exciting progress has been made in understanding how AAA(+) machines recognize specific proteins as targets and then carry out ATP-dependent dismantling of the tertiary and/or quaternary structure of these molecules during the processes of protein degradation and the disassembly of macromolecular complexes.

...read moreread less

460 citations

"m‐AAA protease‐driven membrane disl..." refers background in this paper

...Conserved residues in the pore loop are essential for Ccp1 processing Most AAAþ proteins form hexameric ring structures that allow substrates to enter the central channel (Sauer et al, 2004; Hanson and Whiteheart, 2005)....
[...]
...At the same time, they conduct the quality surveillance of cellular proteins and degrade misfolded proteins to peptides (Sauer et al, 2004; Ciechanover, 2005; Hanson and Whiteheart, 2005)....
[...]
...ATP-dependent unfolding of substrates allows substrate entry into barrel-like proteolytic chambers and results in complete degradation (Sauer et al, 2004)....
[...]
...This loop contains an aromatichydrophobic-glycine motif (FVG in Yta10 and Yta12), which is conserved within AAAþ proteins (Figure 7A) and has been linked to substrate translocation in other AAA proteins (Sauer et al, 2004; Hanson and Whiteheart, 2005)....
[...]