Evolutionary conservation of biogenesis of β-barrel membrane proteins

Paschen, Stefan A.; Waizenegger, Thomas; Stan, Tincuta; Preuss, Marc; Cyrklaff, Marek; Hell, Kai; Rapaport, Doron; Neupert, Walter

doi:10.1038/nature02208

Cited by 394 publications

(464 citation statements)

References 29 publications

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“…60 Tob55/Sam50 channel is~7-8 nm large enough to accommodate the 16-22 β-strands of a β-barrel protein. 61 It is even speculated to work as an oligomer to facilitate the lateral release of the β-barrel protein being membrane-inserted, which in this context could increase its channel cutoff. 62,63 However, even as a monomer this channel is large enough to accommodate the 3.5x5 nm diameter of the GB ellipsoid.…”

Section: Discussionmentioning

confidence: 99%

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Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis

et al. 2017

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We have found that granzyme B (GB)-induced apoptosis also requires reactive oxygen species resulting from the alteration of mitochondrial complex I. How GB, which does not possess a mitochondrial targeting sequence, enter this organelle is unknown. We show that GB enters the mitochondria independently of the translocase of the outer mitochondrial membrane complex, but requires instead Sam50, the central subunit of the sorting and assembly machinery that integrates outer membrane β-barrel proteins. Moreover, GB breaches the inner membrane through Tim22, the metabolite carrier translocase pore, in a mitochondrial heat-shock protein 70 (mtHsp70)-dependent manner. Granzyme A (GA) and caspase-3 use a similar route to the mitochondria. Finally, preventing GB from entering the mitochondria either by mutating lysine 243 and arginine 244 or depleting Sam50 renders cells more resistant to GB-mediated reactive oxygen species and cell death. Similarly, Sam50 depletion protects cells from GA-, GM-and caspase-3-mediated cell death. Therefore, cytotoxic molecules enter the mitochondria to induce efficiently cell death through a noncanonical Sam50-, Tim22-and mtHsp70-dependent import pathway.Cytotoxic lymphocytes eradicate pathogen-infected or transformed cells mainly through the cytotoxic granule pathway. [1][2][3][4] Among the five human granzymes (A, B, H, K and M), granzyme B (GB) triggers cell death in both a caspasedependent and caspase-independent manner, although human and mouse GB differ in their requirement for caspase activation. 5-10 GB-induced cell death also involves Bid/Bax/ Bak-mediated mitochondrial outer membrane permeabilization for the release of the apoptogenic factors cytochrome c, Smac/Diablo, Endo G, HtrA2 and AIF. 1,9-17 We have recently reported that mitochondrial reactive oxygen species (ROS) have a critical role in GB pathway by amplifying apoptogenic factor release, oligonucleosomal DNA fragmentation and lysosomal membrane rupture. 18 Mitochondrial ROS resulted from GB-mediated cleavage of NDUFV1, NDUFS1 and NDUFS2, three subunits of mitochondrial complex I. 18 How GB that does not possess a mitochondrial targeting sequence enters the mitochondria is not known. The mitochondrial nucleoid encodes only for 13 structural proteins, while the rest of the mitochondrial proteome is nuclear-encoded and transported to the mitochondria through a sophisticated protein import machinery. [19][20][21][22][23][24][25][26][27][28] The translocase of the outer mitochondrial membrane (TOM), the entry gate to the mitochondria, 20 passes on the cargos to the sorting and assembly machinery (SAM) complex, to the mitochondrial intermembrane space assembly (MIA) complex and to the translocases of the inner mitochondrial membrane TIM22 or TIM23 complexes for delivery to the outer membrane, the intermembrane space, the inner membrane or the matrix, respectively. [19][20][21][22]25,26,28 Unexpectedly, we found that GB mitochondrial entry is independent of the TOM-TIM23 complexes, but requires instead the Sam50 and Tim22 chann...

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Section: Discussionmentioning

confidence: 99%

“…38 Interestingly, in agreement with our findings, it was previously reported that Tob55/Sam50 channel could have a role in apoptosis. 61,64 Tim22 and mtHsp70 are required for granzyme to cross the inner membrane. Tim22 is the core channel of the metabolite carrier translocase complex.…”

Section: Discussionmentioning

confidence: 99%

Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis

et al. 2017

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“…Our findings suggest that Taz1 follows the same transport pathway as carrier proteins and ␤-barrel proteins across the outer membrane. However, although further transport of ␤-barrel proteins requires the SAM complex Kozjak et al, 2003;Paschen et al, 2003) Taz1 transport was independent of the SAM complex. Thus, import, fractionation, and analysis of the biogenesis support an outer membrane localization for Taz1.…”

Section: Taz1 and Respiratory Chain Complexesmentioning

confidence: 99%

“…To do this, we developed a BN-PAGE based assay to analyze assembly of newly imported subunits of complex IV into preexisting protein complexes. Similar import and assembly assays have successfully been used to assess outer membrane protein complex biogenesis (Krimmer et al, 2001;Model et al, 2001;Kozjak et al, 2003;Paschen et al, 2003;Wiedemann et al, 2003). Newly imported Cox5a assembled into the complex Figure 6.…”

Section: Taz1 and Respiratory Chain Complexesmentioning

confidence: 99%

Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

Brandner

Mick

Frazier

et al. 2005

MBoC

190

150

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The Saccharomyces cerevisiae Taz1 protein is the orthologue of human Tafazzin, a protein that when inactive causes Barth Syndrome (BTHS), a severe inherited X-linked disease. Taz1 is a mitochondrial acyltransferase involved in the remodeling of cardiolipin. We show that Taz1 is an outer mitochondrial membrane protein exposed to the intermembrane space (IMS). Transport of Taz1 into mitochondria depends on the receptor Tom5 of the translocase of the outer membrane (TOM complex) and the small Tim proteins of the IMS, but is independent of the sorting and assembly complex (SAM). TAZ1 deletion in yeast leads to growth defects on nonfermentable carbon sources, indicative of a defect in respiration. Because cardiolipin has been proposed to stabilize supercomplexes of the respiratory chain complexes III and IV, we assess supercomplexes in taz1⌬ mitochondria and show that these are destabilized in taz1⌬ mitochondria. This leads to a selective release of a complex IV monomer from the III 2 IV 2 supercomplex. In addition, assembly analyses of newly imported subunits into complex IV show that incorporation of the complex IV monomer into supercomplexes is affected in taz1⌬ mitochondria. We conclude that inactivation of Taz1 affects both assembly and stability of respiratory chain complexes in the inner membrane of mitochondria. INTRODUCTIONBarth Syndrome is an X-linked recessive disorder that is characterized by cardioskeletal myopathy, neutropenia, increased urine levels of 3-methylglutaconic acid, abnormal mitochondria, and respiratory chain dysfunction (Barth et al., 1983(Barth et al., , 1996Kelley et al., 1991;D'Adamo et al., 1997). The disease is often fatal in infancy and early childhood because of cardiac failure and bacterial infections (Barth et al., 2004). Bione et al. (1996) identified the gene responsible, termed Tafazzin (TAZ), and localized it to region q28 on the X chromosome. Sequence analyses demonstrate that the Taz protein is highly conserved from yeast to man and that it displays sequence similarity to acyltransferases that participate in the metabolism of phospholipids (Neuwald, 1997). Phospholipid analyses of fibroblasts from patients and yeast taz1⌬ mutant cells show reduced cardiolipin levels and an altered acyl chain composition (Vreken et al., 2000;Vaz et al., 2003;Xu et al., 2003;Gu et al., 2004).Cardiolipin is formed by two glycerol-linked phosphatidyl moieties. The four acyl side chains are usually monoand di-unsaturated fatty acids in higher eukaryotes. Remodeling of cardiolipin through a cycle of deacylation and successive reacylation leads to the final and specific acyl composition. In heart and skeletal muscle mitochondria the tetralinoleoyl species predominates Xu et al., 2003;Hatch, 2004). Cardiolipin is primarily found in the mitochondrial membranes of eukaryotes (Hoch, 1992) and the bacterial cytoplasmic membrane. Although the molecular function of cardiolipin is still unclear, several studies have suggested that it is required for the proper function of some proteins and protein complexe...

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“…13) and the chloroplast proteins Toc75-III and Toc75-V/Oep80 (14). Remarkably, all three are essential as mutations such as sam50 in yeast and toc75-III or toc75-V are lethal (15)(16)(17).…”

mentioning

confidence: 99%

Chloroplast Omp85 proteins change orientation during evolution

Sommer

Daum

Groß

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The majority of outer membrane proteins (OMPs) from Gramnegative bacteria and many of mitochondria and chloroplasts are β-barrels. Insertion and assembly of these proteins are catalyzed by the Omp85 protein family in a seemingly conserved process. All members of this family exhibit a characteristic N-terminal polypeptide-transport-associated (POTRA) and a C-terminal 16-stranded β-barrel domain. In plants, two phylogenetically distinct and essential Omp85's exist in the chloroplast outer membrane, namely Toc75-III and Toc75-V. Whereas Toc75-V, similar to the mitochondrial Sam50, is thought to possess the original bacterial function, its homolog, Toc75-III, evolved to the pore-forming unit of the TOC translocon for preprotein import. In all current models of OMP biogenesis and preprotein translocation, a topology of Omp85 with the POTRA domain in the periplasm or intermembrane space is assumed. Using selfassembly GFP-based in vivo experiments and in situ topology studies by electron cryotomography, we show that the POTRA domains of both Toc75-III and Toc75-V are exposed to the cytoplasm. This unexpected finding explains many experimental observations and requires a reevaluation of current models of OMP biogenesis and TOC complex function.

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Evolutionary conservation of biogenesis of β-barrel membrane proteins

Cited by 394 publications

References 29 publications

Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis

Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis

Taz1, an Outer Mitochondrial Membrane Protein, Affects Stability and Assembly of Inner Membrane Protein Complexes: Implications for Barth Syndrome

Chloroplast Omp85 proteins change orientation during evolution

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