An Internal EELD Domain Facilitates Mitochondrial Targeting of Mcl-1 via a Tom70-dependent Pathway

Chou, Chiang-Hung; Lee, Ru-Shuo; Yang-Yen, Hsin-Fang

doi:10.1091/mbc.e06-04-0319

Cited by 41 publications

(42 citation statements)

References 41 publications

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“…In contrast, we find that Mcl-1⌬N is anchored in the outer membrane and exposed to the cytoplasm, consistent with the earlier findings that the Mcl-1 C-terminal transmembrane (TM) segment is both necessary and sufficient to target and insert Mcl-1 into the outer membrane lipid bilayer (32). Thus, removal of the N-terminal 2-30 aa of Mcl-1 did not interfere with the ability of ectopic expressed Mcl-1⌬N2-30 to target and localize to mitochondria in transfected cells (Fig.…”

Section: Mcl-1 and Mcl-1⌬n Are Located In The Mitochondrial Outersupporting

confidence: 92%

Mitochondrion-dependent N-terminal Processing of Outer Membrane Mcl-1 Protein Removes an Essential Mule/Lasu1 Protein-binding Site

Warr

Mills

Nguyen

et al. 2011

Journal of Biological Chemistry

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Section: Mcl-1 and Mcl-1⌬n Are Located In The Mitochondrial Outersupporting

confidence: 92%

Mitochondrion-dependent N-terminal Processing of Outer Membrane Mcl-1 Protein Removes an Essential Mule/Lasu1 Protein-binding Site

Warr

Mills

Nguyen

et al. 2011

Journal of Biological Chemistry

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“…A yeast two-hybrid interaction between rat Tom70 and Tom20 was reported but not further characterized (27). However, recent work with the mammalian receptors showed that they interact with unexpected binding partners, such as the interaction of Tom70 with the internal EELD sequence of Mcl-1 and that of Tom20 with the TPR cochaperone AIP (14,28). A putative import receptor in mammals, Tom34, was also shown to interact with the chaperone Hsp90 via its TPR clamp domain, although the role of this receptor in preprotein import remains controversial (40 -44).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to importing many inner membrane carrier proteins, Tom70 is also implicated in targeting Mcl-1 to the outer membrane via an internal EELD sequence (14).…”

mentioning

confidence: 99%

Interaction between the Human Mitochondrial Import Receptors Tom20 and Tom70 in Vitro Suggests a Chaperone Displacement Mechanism

Fan

Kozlov

Hoegl

et al. 2011

Journal of Biological Chemistry

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The mitochondrial import receptor Tom70 contains a tetratricopeptide repeat (TPR) clamp domain, which allows the receptor to interact with the molecular chaperones, Hsc70/ Hsp70 and Hsp90. Preprotein recognition by Tom70, a critical step to initiate import, is dependent on these cytosolic chaperones. Preproteins are subsequently released from the receptor for translocation across the outer membrane, yet the mechanism of this step is unknown. Here, we report that Tom20 interacts with the TPR clamp domain of Tom70 via a conserved C-terminal DDVE motif. This interaction was observed by cross-linking endogenous proteins on the outer membrane of mitochondria from HeLa cells and in co-precipitation and NMR titrations with purified proteins. Upon mutation of the TPR clamp domain or deletion of the DDVE motif, the interaction was impaired. In co-precipitation experiments, the Tom20-Tom70 interaction was inhibited by C-terminal peptides from Tom20, as well as from Hsc70 and Hsp90. The Hsp90-Tom70 interaction was measured with surface plasmon resonance, and the same peptides inhibited the interaction. Thus, Tom20 competes with the chaperones for Tom70 binding. Interestingly, antibody blocking of Tom20 did not increase the efficiency of Tom70-dependent preprotein import; instead, it impaired the Tom70 import pathway in addition to the Tom20 pathway. The functional interaction between Tom20 and Tom70 may be required at a later step of the Tom70-mediated import, after chaperone docking. We suggest a novel model in which Tom20 binds Tom70 to facilitate preprotein release from the chaperones by competition.

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“…Studies indicate that both Tom20 and 22 recognize a consensus motif or presequence represented by ϕXXϕϕ (where ϕ is a hydrophobic amino acid such as leucine, isoleucine, phenylalanine, tryptophan, valine, and tyrosine, and × is any amino acid) (Pfanner, 2000;Mukhopadhyay et al, 2006;Saitoh et al, 2007). While peptide mobility within the binding grove of Tom20 also allows binding of alternative sequences, there is a hydrophobic preference for LXXLL (Chou et al, 2006;Mukhopadhyay et al, 2006;Neupert and Herrmann, 2007;Saitoh et al, 2007).…”

Section: Mitochondrial Trafficking Of Erβmentioning

confidence: 99%

Estrogen actions on mitochondria—Physiological and pathological implications

Simpkins

Yang

Sarkar

et al. 2008

Molecular and Cellular Endocrinology

135

105

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Estrogens are potent neuroprotective hormones and mitochondria are the site of cellular life-death decisions. As such, it is not surprising that we and other have shown that estrogens have remarkable effects on mitochondrial function. Herein we provide evidence for a primary effect of estrogens on mitochondrial function, achieved in part by the import of estrogen receptor β (ERβ) into the mitochondria where it mediates a number of estrogen actions on this vital organelle. ERβ is imported into the mitochondria, through tethering to cytosolic chaperone protein and/or through direct interaction with mitochondrial import proteins. In the mitochondria, ERβ can affect transcription of critical mitochondrial genes through the interaction with estrogen response elements (ERE) or through protein-protein interactions with mitochondrially imported transcription factors. The potent effects of estrogens on mitochondrial function, particularly during mitochondrial stress, argues for a role of estrogens in the treatment of mitochondrial defects in chronic neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) and more acute conditions of mitochondrial compromise, like cerebral ischemia and traumatic brain injury.

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An Internal EELD Domain Facilitates Mitochondrial Targeting of Mcl-1 via a Tom70-dependent Pathway

Cited by 41 publications

References 41 publications

Mitochondrion-dependent N-terminal Processing of Outer Membrane Mcl-1 Protein Removes an Essential Mule/Lasu1 Protein-binding Site

Mitochondrion-dependent N-terminal Processing of Outer Membrane Mcl-1 Protein Removes an Essential Mule/Lasu1 Protein-binding Site

Interaction between the Human Mitochondrial Import Receptors Tom20 and Tom70 in Vitro Suggests a Chaperone Displacement Mechanism

Estrogen actions on mitochondria—Physiological and pathological implications

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