Crystal Structures of the CERT START Domain with Inhibitors Provide Insights into the Mechanism of Ceramide Transfer

Kudo, Norio; Kumagai, Keigo; Matsubara, Ryosuke; Kobayashi, Shū; Hanada, Kentaro; Wakatsuki, Soichi; Kato, Ryuichi

doi:10.1016/j.jmb.2009.12.029

Cited by 66 publications

(64 citation statements)

References 14 publications

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“…A detailed description of the proposed model for ceramide transfer by STARD11/CERT has been presented (Hanada et al 2009) and the basic concept is the orientation of the protein with the N-terminus bound to the Golgi membrane and the middle region bound to the ER would place the START domain in close proximity to both membranes to facilitate ceramide extraction from the ER and delivery to the Golgi. The crystal structure of the STARD11/CERT START domain confirmed the helix-grip fold structure for ceramide binding and supports a mechanism for membrane interaction and ceramide extraction/absorption (Kudo et al 2008(Kudo et al , 2010.…”

Section: Stard11/cert: a Ceramide-binding Proteinsupporting

confidence: 52%

The mammalian START domain protein family in lipid transport in health and disease

Clark¹

2011

Journal of Endocrinology

131

106

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Lipid transfer proteins of the steroidogenic acute regulatory protein-related lipid transfer (START) domain family are defined by the presence of a conserved w210 amino acid sequence that folds into an a/b helix-grip structure forming a hydrophobic pocket for ligand binding. The mammalian START proteins bind diverse ligands, such as cholesterol, oxysterols, phospholipids, sphingolipids, and possibly fatty acids, and have putative roles in non-vesicular lipid transport, thioesterase enzymatic activity, and tumor suppression. However, the biological functions of many members of the START domain protein family are not well established. Recent research has focused on characterizing the cell-type distribution and regulation of the START proteins, examining the specificity and directionality of lipid transport, and identifying disease states associated with dysregulation of START protein expression. This review summarizes the current concepts of the proposed physiological and pathological roles for the mammalian START domain proteins in cholesterol and lipid trafficking.

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Section: Stard11/cert: a Ceramide-binding Proteinsupporting

confidence: 52%

The mammalian START domain protein family in lipid transport in health and disease

Clark¹

2011

Journal of Endocrinology

131

106

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“…In addition, overproduction of VAP-A in either mitoCERTor mitoCERTΔSTART-expressing cells greatly expanded the contact area between ER and mitochondria without having any impact on cell fate. Moreover, mitoCERT-induced apoptosis was effectively blocked by HPA12, an antagonistic inhibitor of CERT-mediated ceramide trafficking (Kudo et al, 2010;Kumagai et al, 2005). Thus, a ceramide transfer-competent form of mitoCERT capable of bridging the cytoplasmic gap between mitochondria and ER proved critical for apoptosis induction.…”

Section: Discussionmentioning

confidence: 98%

Diverting CERT-mediated ceramide transport to mitochondria triggers Bax-dependent apoptosis

Jain

Beutel

Ebell

et al. 2017

Journal of Cell Science

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A deregulation of ceramide biosynthesis in the endoplasmic reticulum (ER) is frequently linked to induction of mitochondrial apoptosis. Although in vitro studies suggest that ceramides might initiate cell death by acting directly on mitochondria, their actual contribution to the apoptotic response in living cells is unclear. Here, we have analyzed the consequences of targeting the biosynthetic flow of ceramides to mitochondria using a ceramide transfer protein (encoded by COL4A3BP) equipped with an OMM anchor, mitoCERT. Cells expressing mitoCERT import ceramides into mitochondria and undergo Bax-dependent apoptosis. Apoptosis induction by mitoCERT was abolished through (i) removal of its ceramide transfer domain, (ii) disruption of its interaction with VAMPassociated proteins (VAPs) in the ER, (iii) addition of antagonistic CERT inhibitor HPA12, (iv) blocking de novo ceramide synthesis and (v) targeting of a bacterial ceramidase to mitochondria. Our data provide the first demonstration that translocation of ER ceramides to mitochondria specifically commits cells to death and establish mitoCERT as a valuable new tool to unravel the molecular principles underlying ceramide-mediated apoptosis.

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“…This domain is essential for the activities, as the deletion of the START domain impairs the CERT ceramide transfer activity (4). Recently, the three-dimensional structure of the CERT START domain was determined by x-ray crystallography (6), and the molecular mechanisms for its membrane interaction, and subsequent ceramide extraction, were revealed (7,8).…”

mentioning

confidence: 99%

Structural Basis for the Golgi Association by the Pleckstrin Homology Domain of the Ceramide Trafficking Protein (CERT)

Sugiki

Takeuchi

Yamaji

et al. 2012

Journal of Biological Chemistry

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Background:The CERT PH domain is indispensable for the ER-to-Golgi ceramide transport. Results: The three-dimensional structure and interaction study revealed the Golgi recognition mode of the CERT PH domain. Conclusion:The basic groove in the CERT PH domain plays a critical role in the Golgi recognition. Significance: Conservation of the basic groove within lipid transporters uncovers functional significance of the structural motif.

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Crystal Structures of the CERT START Domain with Inhibitors Provide Insights into the Mechanism of Ceramide Transfer

Cited by 66 publications

References 14 publications

The mammalian START domain protein family in lipid transport in health and disease

The mammalian START domain protein family in lipid transport in health and disease

Diverting CERT-mediated ceramide transport to mitochondria triggers Bax-dependent apoptosis

Structural Basis for the Golgi Association by the Pleckstrin Homology Domain of the Ceramide Trafficking Protein (CERT)

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