Structural comparison of yeast and human intra-mitochondrial lipid transport systems

Miliara, Xeni; Matthews, Stephen

doi:10.1042/bst20150264

Cited by 6 publications

(3 citation statements)

References 19 publications

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“…We discovered that residues W65 and F69 of the α2-loop would be inserted into the membrane alternately during PA transfer. Although Miliara et al suggested that the α3-helix and the Ω-loop (here, α2-loop) undergo subtle conformational changes, potentially contributing to phospholipid binding and release 26 and speculated that conformational differences in the Ω-loop (here, α2-loop) and α3helix between PRELID1 and PRELID3b are potentially important for lipid specificity 23 , no experimental data have supported this finding. Our disulfide-bridge experiments not only verified these conformational changes but also suggest a synergistic conformational change between the α2-loop and N-α3-helix.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism of mitochondrial phosphatidate transfer by Ups1

Chan

et al. 2020

Commun Biol

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Cardiolipin, an essential mitochondrial physiological regulator, is synthesized from phosphatidic acid (PA) in the inner mitochondrial membrane (IMM). PA is synthesized in the endoplasmic reticulum and transferred to the IMM via the outer mitochondrial membrane (OMM) under mediation by the Ups1/Mdm35 protein family. Despite the availability of numerous crystal structures, the detailed mechanism underlying PA transfer between mitochondrial membranes remains unclear. Here, a model of Ups1/Mdm35-membrane interaction is established using combined crystallographic data, all-atom molecular dynamics simulations, extensive structural comparisons, and biophysical assays. The α2-loop, L2-loop, and α3 helix of Ups1 mediate membrane interactions. Moreover, non-complexed Ups1 on membranes is found to be a key transition state for PA transfer. The membrane-bound noncomplexed Ups1/ membrane-bound Ups1 ratio, which can be regulated by environmental pH, is inversely correlated with the PA transfer activity of Ups1/Mdm35. These results demonstrate a new model of the fine conformational changes of Ups1/Mdm35 during PA transfer.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanism of mitochondrial phosphatidate transfer by Ups1

Chan

et al. 2020

Commun Biol

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“…TRIAP1 is a homolog of MDM35, the sequence and structure of the two are similar, but the N‐terminus of MDM35 also has a short α‐helix, and the C‐terminus is more flexible than TRIAP1 (Figure 3). 367 Similar to MDM35, 368 TRIAP1 can form a heterodimer with protein of relevant evolutionary and lymphoid interest (PRELI) protein and play the role of transporting phospholipids in the mitochondrial intermembrane space 369 . TRIAP1 can inhibit mitochondrial cleavage and the activation of downstream apoptotic protease activating factor‐1 (APAF1)/apoptosome, and play an antiapoptotic effect 370 .…”

Section: Oncogene Triap1: a Novel Target Downstream Of P53mentioning

confidence: 99%

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

Shen¹,

Wang²,

Mao³

et al. 2023

MedComm

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Tumor suppressor p53 can transcriptionally activate downstream genes in response to stress, and then regulate the cell cycle, DNA repair, metabolism, angiogenesis, apoptosis, and other biological responses. p53 has seven functional domains and 12 splice isoforms, and different domains and subtypes play different roles. The activation and inactivation of p53 are finely regulated and are associated with phosphorylation/acetylation modification and ubiquitination modification, respectively. Abnormal activation of p53 is closely related to the occurrence and development of cancer. While targeted therapy of the p53 signaling pathway is still in its early stages and only a few drugs or treatments have entered clinical trials, the development of new drugs and ongoing clinical trials are expected to lead to the widespread use of p53 signaling‐targeted therapy in cancer treatment in the future. TRIAP1 is a novel p53 downstream inhibitor of apoptosis. TRIAP1 is the homolog of yeast mitochondrial intermembrane protein MDM35, which can play a tumor‐promoting role by blocking the mitochondria‐dependent apoptosis pathway. This work provides a systematic overview of recent basic research and clinical progress in the p53 signaling pathway and proposes that TRIAP1 is an important therapeutic target downstream of p53 signaling.

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“…While structural analyses and in vitro assays have clearly shown that TRIAP1 interacts with the evolutionary-conserved members of the PRELI family (PRELID1, PRELID3A, and PRELID3B) and is fully capable of carrying out lipid transfer activities for PA and PS, understanding the regulation and the physiological relevance of its mitochondrial action in human cells is still in its infancy (18,(26)(27)(28). The perturbation of TRIAP1/PRELID1-mediated lipid transfer alters the response to apoptotic signals, as it has been reported that knockdown of either TRIAP1 or PRELID1 in HeLa cells partially reduces CL levels, favors the release of cytochrome c, and increases the vulnerability of the cells to apoptosis (26).…”

Section: Introductionmentioning

confidence: 99%

Relevance of the TRIAP1/p53 axis in colon cancer cell proliferation and adaptation to glutamine deprivation

et al. 2022

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Human TRIAP1 (TP53-regulated inhibitor of apoptosis 1; also known as p53CSV for p53-inducible cell survival factor) is the homolog of yeast Mdm35, a well-known chaperone that interacts with the Ups/PRELI family proteins and participates in the intramitochondrial transfer of lipids for the synthesis of cardiolipin (CL) and phosphatidylethanolamine. Although recent reports indicate that TRIAP1 is a prosurvival factor abnormally overexpressed in various types of cancer, knowledge about its molecular and metabolic function in human cells is still elusive. It is therefore critical to understand the metabolic and proliferative advantages that TRIAP1 expression provides to cancer cells. Here, in a colorectal cancer cell model, we report that the expression of TRIAP1 supports cancer cell proliferation and tumorigenesis. Depletion of TRIAP1 perturbed the mitochondrial ultrastructure, without a major impact on CL levels and mitochondrial activity. TRIAP1 depletion caused extramitochondrial perturbations resulting in changes in the endoplasmic reticulum-dependent lipid homeostasis and induction of a p53-mediated stress response. Furthermore, we observed that TRIAP1 depletion conferred a robust p53-mediated resistance to the metabolic stress caused by glutamine deprivation. These findings highlight the importance of TRIAP1 in tumorigenesis and indicate that the loss of TRIAP1 has extramitochondrial consequences that could impact on the metabolic plasticity of cancer cells and their response to conditions of nutrient deprivation.

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Structural comparison of yeast and human intra-mitochondrial lipid transport systems

Cited by 6 publications

References 19 publications

Molecular mechanism of mitochondrial phosphatidate transfer by Ups1

Molecular mechanism of mitochondrial phosphatidate transfer by Ups1

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

Relevance of the TRIAP1/p53 axis in colon cancer cell proliferation and adaptation to glutamine deprivation

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