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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Journal Article•DOI•

A Mitochondrial Odyssey

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Walter Neupert¹•Institutions (1)

Max Planck Society¹

04 Jun 2012-Annual Review of Biochemistry

TL;DR: Good fortune let me be an innocent child during World War II, a hopeful adolescent with encouraging parents during the years of German recovery, and a self-determined adult in a period of peace, freedom, and wealth as a scientist who could entirely follow his fancy.

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Abstract: Good fortune let me be an innocent child during World War II, a hopeful adolescent with encouraging parents during the years of German recovery, and a self-determined adult in a period of peace, freedom, and wealth. My luck continued as a scientist who could entirely follow his fancy. My mind was always set on understanding how things are made. At a certain point, I found myself confronted with the question of how mitochondria and organelles, which cannot be formed de novo, are put together. Intracellular transport of proteins, their translocation across the mitochondrial membranes, and their folding and assembly were the processes that fascinated me. Now, after some 30 years, we have wonderful insights, unimagined views of a complex and at the same time simple machinery and its workings. We have glimpses of how orderly processes are established in the cell to assemble from single molecules our beautiful mitochondria that every day make some 50 kg of ATP for each of us. At the same time, we have learned a...

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11 citations

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

...The m-AAA ATPase was found to play a role in the topogenesis of yeast cytochrome c peroxidase (112)....
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Posted Content•DOI•

Atomic structure of the mitochondrial inner membrane AAA+ protease YME1 reveals the mechanism of substrate processing

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Cristina Puchades¹, Anthony J. Rampello², Mia Shin¹, Christopher J. Giuliano², R. Luke Wiseman², Steven E. Glynn², Gabriel C. Lander¹ - Show less +3 more•Institutions (2)

Scripps Research Institute¹, Stony Brook University²

15 Sep 2017-bioRxiv

TL;DR: The first atomic model of a substrate-bound inner mitochondrial membrane AAA+ quality control protease, YME1, is presented and a translocation mechanism likely conserved for other AAA+ ATPases is revealed.

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Abstract: We present the first atomic model of a substrate-bound inner mitochondrial membrane AAA+ quality control protease, YME1. Our ~3.4 A cryo-EM structure reveals how the ATPases form a closed spiral staircase encircling an unfolded substrate, directing it toward the flat, symmetric protease ring. Importantly, the structure reveals how three coexisting nucleotide states allosterically induce distinct positioning of tyrosines in the central channel, resulting in substrate engagement and translocation to the negatively charged proteolytic chamber. This tight coordination by a network of conserved residues defines a sequential, around-the-ring ATP hydrolysis cycle that results in step-wise substrate translocation. Furthermore, we identify a hinge-like linker that accommodates the large-scale nucleotide-driven motions of the ATPase spiral independently of the contiguous planar proteolytic base. These results define the first molecular mechanism for a mitochondrial inner membrane AAA+ protease and reveal a translocation mechanism likely conserved for other AAA+ ATPases.

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10 citations

Journal Article•DOI•

A Force-Generating Machine in the Plant's Powerhouse: A Pulling AAA-ATPase Motor Drives Protein Translocation into Chloroplasts.

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Johannes M. Herrmann¹•Institutions (1)

Kaiserslautern University of Technology¹

01 Nov 2018-The Plant Cell

TL;DR: Most chloroplast proteins are encoded by the nuclear genome and synthesized on cytosolic ribosomes and N-terminal transit peptides serve as targeting sequences to direct precursor proteins to receptors on thechloroplast surface.

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Abstract: Most chloroplast proteins are encoded by the nuclear genome and synthesized on cytosolic ribosomes. N-terminal transit peptides serve as targeting sequences to direct precursors of chloroplast proteins to receptors on the chloroplast surface. These receptors are part of the translocase of the outer

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8 citations

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

...Import of the mitochondrial protein Pcp1 requires the mitochondrial m-AAA protease, which is a homolog of the newly discovered chloroplast AAA-ATPase motor (Tatsuta et al., 2007)....
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Journal Article•DOI•

Mitochondrial AAA proteases: A stairway to degradation

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Tyler E. Steele¹, Steven E. Glynn¹•Institutions (1)

Stony Brook University¹

01 Nov 2019-Mitochondrion

TL;DR: Together, these studies have revealed the mechanics of ATP-driven protein destruction and significantly advanced the authors' understanding of how these proteases maintain mitochondrial health.

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8 citations

Journal Article•DOI•

Molecular insights into the m-AAA protease–mediated dislocation of transmembrane helices in the mitochondrial inner membrane

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Seoeun Lee¹, Hunsang Lee¹, Suji Yoo¹, Hyun Kim¹•Institutions (1)

Seoul National University¹

08 Dec 2017-Journal of Biological Chemistry

TL;DR: This study investigated the role of the TM domains in the m-AAA protease by systematic replacement of one TM domain at a time in yeast and highlighted previously underappreciated biological roles of TM domains of the m -AAA proteases in mediating the recognition and dislocation of membrane-embedded substrates.

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8 citations

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

...In the case of Ccp1 maturation, the m-AAA protease acts as an ATPase by pulling the Ccp1 TM to the matrix prior to processing by a rhomboid protease, Pcp1, in the IM (10, 11)....
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...The function of the m-AAA proteases is not limited to quality control, but it also assists with protein folding of a mitochondrial ribosome subunit, MrpL32 (9), and maturation of cytochrome c peroxidase (Ccp1) (10)....
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Journal Article•DOI•

AAA+ proteins: have engine, will work.

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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.

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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.

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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)....
[...]