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•

Mitochondrial AAA proteases--towards a molecular understanding of membrane-bound proteolytic machines.

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Florian Gerdes¹, Takashi Tatsuta¹, Thomas Langer¹, Thomas Langer²•Institutions (2)

University of Cologne¹, Max Planck Society²

01 Jan 2012-Biochimica et Biophysica Acta

TL;DR: Recent findings on the molecular mechanisms underlying the versatile functions of mitochondrial AAA proteases and their relevance to those of the other AAA+ machines are summarized.

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117 citations

Journal Article•DOI•

The Rhomboid-Like Superfamily: Molecular Mechanisms and Biological Roles

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Matthew Freeman¹•Institutions (1)

University of Oxford¹

06 Oct 2014-Annual Review of Cell and Developmental Biology

TL;DR: The rhomboid proteases were first discovered as regulators of Drosophila EGF receptor signaling; soon after, it was recognized that they represented the founder members of a widespread family of intramembrane serine proteases conserved in all kingdoms.

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Abstract: The rhomboid proteases were first discovered as regulators of Drosophila EGF receptor signaling; soon after, it was recognized that they represented the founder members of a widespread family of intramembrane serine proteases conserved in all kingdoms. More recently still, the family was promoted to a superfamily, encompassing a wide variety of distantly related proteins. One of the surprises has been that many members of the rhomboid-like superfamily are not active proteases. Given the size of this clan, and its relatively recent discovery, there is still much to learn. Nevertheless, we already understand much about how rhomboid proteases perform their surprising function of cleaving transmembrane domains. We also already know that members of the rhomboid-like superfamily participate in biological functions as diverse as growth factor signaling, mitochondrial dynamics, inflammation, parasite invasion, and the machinery of protein quality control. Their potential medical significance is now becoming apparent in several areas.

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109 citations

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

...Recently, however, two chloroplast localised rhomboids have been investigated and shown to affect flower development, possibly by regulating the levels of allene oxide synthase (Knopf et al., 2012; Thompson et al., 2012)....
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Journal Article•DOI•

The structural basis for catalysis and substrate specificity of a rhomboid protease

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Kutti R. Vinothkumar¹, Kvido Strisovsky¹, Antonina Andreeva¹, Yonka Christova¹, Steven H. L. Verhelst², Matthew Freeman¹ - Show less +2 more•Institutions (2)

Laboratory of Molecular Biology¹, Center for Integrated Protein Science Munich²

17 Nov 2010-The EMBO Journal

TL;DR: This study describes the structure of Escherichia coli rhomboid GlpG covalently bound to a mechanism‐based isocoumarin inhibitor, and identifies the position of the oxyanion hole, and the S1‐ and S2′‐binding subsites of Gl pG, which are the key determinants of substrate specificity.

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Abstract: Rhomboids are intramembrane proteases that use a catalytic dyad of serine and histidine for proteolysis. They are conserved in both prokaryotes and eukaryotes and regulate cellular processes as diverse as intercellular signalling, parasitic invasion of host cells, and mitochondrial morphology. Their widespread biological significance and consequent medical potential provides a strong incentive to understand the mechanism of these unusual enzymes for identification of specific inhibitors. In this study, we describe the structure of Escherichia coli rhomboid GlpG covalently bound to a mechanism-based isocoumarin inhibitor. We identify the position of the oxyanion hole, and the S1- and S2′-binding subsites of GlpG, which are the key determinants of substrate specificity. The inhibitor-bound structure suggests that subtle structural change is sufficient for catalysis, as opposed to large changes proposed from previous structures of unliganded GlpG. Using bound inhibitor as a template, we present a model for substrate binding at the active site and biochemically test its validity. This study provides a foundation for a structural explanation of rhomboid specificity and mechanism, and for inhibitor design.

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101 citations

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

...For example, cleavage sites in the mitochondrial rhomboid substrates do not seem to contain a TatA-like recognition motif (Herlan et al, 2003; Tatsuta et al, 2007), and widely different sequences are apparently accepted at their cleavage site (Schafer et al, 2010)....
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Journal Article•DOI•

Emerging roles of mitochondrial proteases in neurodegeneration.

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Paola Martinelli, Elena I. Rugarli¹•Institutions (1)

University of Milano-Bicocca¹

01 Jan 2010-Biochimica et Biophysica Acta

TL;DR: Current knowledge on how disturbances of the mitochondrial proteolytic system affect neuronal maintenance and axonal function is reviewed.

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100 citations

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

...These proteases actively extract transmembrane segments and pull solventexposed domains across the membrane, before exerting proteolytic activity [14,15]....
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Journal Article•DOI•

An Intersubunit Signaling Network Coordinates ATP Hydrolysis by m-AAA Proteases

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Steffen Augustin¹, Florian Gerdes¹, Sukyeong Lee², Francis T.F. Tsai², Thomas Langer¹, Thomas Langer³, Takashi Tatsuta¹ - Show less +3 more•Institutions (3)

University of Cologne¹, Baylor College of Medicine², Max Planck Society³

11 Sep 2009-Molecular Cell

TL;DR: Coordinated ATP hydrolysis within m-AAA protease ring complexes, conserved AAA+ machines in the inner membrane of mitochondria, provides insight into how AAA+ proteins convert energy derived from ATP Hydrolysis into mechanical work.

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98 citations

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

...It depends on ATP hydrolysis but can be mediated by m-AAA variants with low ATPase activity (Tatsuta et al., 2007)....
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...m-AAA protease variants with impaired intersubunit communication exhibit proteolytic activity toward some substrates but cannot handle others, which need to be dislocated from the membrane and therefore require additional energy input (Leonhard et al., 2000; Tatsuta et al., 2007)....
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...Current evidence suggests that conserved loop regions protruding into the central channel of diverse AAA+ rings play a crucial role in these processes (Song et al., 2000; Yamada-Inagawa et al., 2003;Weibezahn et al., 2004;Hinnerwischet al., 2005; DeLaBarre et al., 2006; Tatsuta et al., 2007; Martin et al., 2008)....
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...…pore loop-1 of Yta12 (Figure 4C), which is crucial for substrate translocation through the central pore of many AAA+ ATPases (Song et al., 2000; Yamada-Inagawa et al., 2003; Weibezahn et al., 2004; Hinnerwisch et al., 2005; DeLaBarre et al., 2006; Tatsuta et al., 2007; Martin et al., 2008)....
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...…interacting with substrates in other AAA+ proteins (Song et al., 2000; Yamada-Inagawa et al., 2003; Weibezahn et al., 2004; Hinnerwisch et al., 2005; DeLaBarre et al., 2006; Tatsuta et al., 2007; Martin et al., 2008), alleviate the inhibitory effect and restore proteolysis at least to some extent....
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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)....
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...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)....
[...]