A presequence-binding groove in Tom70 supports import of Mdl1 into mitochondria

Melin, Jonathan; Kilisch, Markus; Neumann, Piotr; Lytovchenko, Oleksandr; Gomkale, Ridhima; Schendzielorz, Alexander Benjamin; Schmidt, Bernhard; Liepold, Thomas; Ficner, Ralf; Jahn, Olaf; Rehling, Peter; Schulz, Christian

doi:10.1016/j.bbamcr.2015.04.021

Cited by 33 publications

(27 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, regardless of the actual mode of interaction it seems that Sti1 is involved in the ternary association of client proteins, chaperones, and Tom70. In this respect, our current findings join a growing number of reports suggesting an involvement of Tom70 not only in the import of multispan membrane proteins with internal targeting signals [10,28] but rather also in the biogenesis of presequence-containing precursor proteins [29][30][31]. Interestingly, it appears that the involvement of Tom70 is required if the mature domains of the preproteins are prone to aggregation [29,30].…”

Section: Discussionsupporting

confidence: 83%

The cytosolic cochaperone Sti1 is relevant for mitochondrial biogenesis and morphology

et al. 2016

View full text Add to dashboard Cite

Most mitochondrial proteins are synthesized in the cytosol prior to their import into the organelle. It is commonly accepted that cytosolic factors are required for delivering precursor proteins to the mitochondrial surface and for keeping newly synthesized proteins in an import-competent conformation. However, the identity of such factors and their defined contribution to the import process are mostly unknown. Using a presequence-containing model protein and a site-directed photo-crosslinking approach in yeast cells we identified the cytosolic chaperones Hsp70 (Ssa1) and Hsp90 (Hsp82) as well as their cochaperones, Sti1 and Ydj1, as putative cytosolic factors involved in mitochondrial protein import. Deletion of STI1 caused both alterations in mitochondrial morphology and lower steady-state levels of a subset of mitochondrial proteins. In addition, double deletion of STI1 with the mitochondrial import factors, MIM1 or TOM20, showed a synthetic growth phenotype indicating a genetic interaction of STI1 with these genes. Moreover, recombinant cytosolic domains of the import receptors Tom20 and Tom70 were able to bind in vitro Sti1 and other cytosolic factors. In summary, our observations point to a, direct or indirect, role of Sti1 for mitochondrial functionality.

show abstract

Section: Discussionsupporting

confidence: 83%

The cytosolic cochaperone Sti1 is relevant for mitochondrial biogenesis and morphology

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Furthermore, our structural model advances our understanding of how the protein client is arranged from C-Hsp90 to the cytosolic domain of Tom70. Previous studies (12,28) have accumulated evidence that a pocket in the C-terminal domain of Tom70 is dedicated to binding of the preprotein. Fig.…”

Section: Resultsmentioning

confidence: 99%

Heat Shock Protein 90 kDa (Hsp90) Has a Second Functional Interaction Site with the Mitochondrial Import Receptor Tom70

Zanphorlin

Lima

Wong

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

To accomplish its crucial role, mitochondria require proteins that are produced in the cytosol, delivered by cytosolic Hsp90, and translocated to its interior by the translocase outer membrane (TOM) complex. Hsp90 is a dimeric molecular chaperone and its function is modulated by its interaction with a large variety of co-chaperones expressed within the cell. An important family of co-chaperones is characterized by the presence of one TPR (tetratricopeptide repeat) domain, which binds to the C-terminal MEEVD motif of Hsp90. These include Tom70, an important component of the TOM complex. Despite a wealth of studies conducted on the relevance of Tom70·Hsp90 complex formation, there is a dearth of information regarding the exact molecular mode of interaction. To help fill this void, we have employed a combined experimental strategy consisting of cross-linking/mass spectrometry to investigate binding of the C-terminal Hsp90 domain to the cytosolic domain of Tom70. This approach has identified a novel region of contact between C-Hsp90 and Tom70, a finding that is confirmed by probing the corresponding peptides derived from cross-linking experiments via isothermal titration calorimetry and mitochondrial import assays. The data generated in this study are combined to input constraints for a molecular model of the Hsp90/Tom70 interaction, which has been validated by small angle x-ray scattering, hydrogen/deuterium exchange, and mass spectrometry. The resultant model suggests that only one of the MEEVD motifs within dimeric Hsp90 contacts Tom70. Collectively, our findings provide significant insight on the mechanisms by which preproteins interact with Hsp90 and are translocated via Tom70 to the mitochondria.

show abstract

“…In comparison to Tom70, Tom71 was found to display a strikingly divergent arrangement of its C- and N-terminal domains. The differences seem to refer to alternative conformational states of both Tom70 and Tom71, including an open and a closed conformation ( Figure 2 B), and this flexibility was suggested to determine the accessibility of a binding site for protein recognition [ 37 , 38 , 39 , 40 ].…”

Section: Molecular Structure Of Tom70mentioning

confidence: 99%

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

Kreimendahl

Rassow

2020

IJMS

View full text Add to dashboard Cite

Tom70 is a versatile adaptor protein of 70 kDa anchored in the outer membrane of mitochondria in metazoa, fungi and amoeba. The tertiary structure was resolved for the Tom70 of yeast, showing 26 α-helices, most of them participating in the formation of 11 tetratricopeptide repeat (TPR) motifs. Tom70 serves as a docking site for cytosolic chaperone proteins and co-chaperones and is thereby involved in the uptake of newly synthesized chaperone-bound proteins in mitochondrial biogenesis. In yeast, Tom70 additionally mediates ER-mitochondria contacts via binding to sterol transporter Lam6/Ltc1. In mammalian cells, TOM70 promotes endoplasmic reticulum (ER) to mitochondria Ca2+ transfer by association with the inositol-1,4,5-triphosphate receptor type 3 (IP3R3). TOM70 is specifically targeted by the Bcl-2-related protein MCL-1 that acts as an anti-apoptotic protein in macrophages infected by intracellular pathogens, but also in many cancer cells. By participating in the recruitment of PINK1 and the E3 ubiquitin ligase Parkin, TOM70 can be implicated in the development of Parkinson’s disease. TOM70 acts as receptor of the mitochondrial antiviral-signaling protein (MAVS) and thereby participates in the corresponding system of innate immunity against viral infections. The protein encoded by Orf9b in the genome of SARS-CoV-2 binds to TOM70, probably compromising the synthesis of type I interferons.

show abstract

A presequence-binding groove in Tom70 supports import of Mdl1 into mitochondria

Cited by 33 publications

References 53 publications

The cytosolic cochaperone Sti1 is relevant for mitochondrial biogenesis and morphology

The cytosolic cochaperone Sti1 is relevant for mitochondrial biogenesis and morphology

Heat Shock Protein 90 kDa (Hsp90) Has a Second Functional Interaction Site with the Mitochondrial Import Receptor Tom70

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

Contact Info

Product

Resources

About