An Environment-dependent Structural Switch Underlies the Regulation of Carnitine Palmitoyltransferase 1A

Rao, Jampani Nageswara; Warren, Gemma; Estolt-Povedano, Sara; Zammit, Victor A.; Ulmer, Tobias S.

doi:10.1074/jbc.m111.306951

Cited by 27 publications

(51 citation statements)

References 65 publications

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“…20 Gene expression, 2 H/ 13 C/ 15 N labeling, and purification of the N domain (Arg37Cys) were carried out as described for the wild-type N domain elsewhere. 21 Two samples, Nα and Nβ, which corresponded to an inhibitory and noninhibitory state in CPT1A, were prepared.…”

Section: Methodsmentioning

confidence: 99%

Mutation inCPT1CAssociated With Pure Autosomal Dominant Spastic Paraplegia

et al. 2015

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The family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients.OBJECTIVE To identify the genetic cause for a novel form of pure autosomal dominant HSP. DESIGN, SETTING, AND PARTICIPANTS We examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened. MAIN OUTCOME AND MEASUREMutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene. RESULTSWe identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) number (213.0 [46.99] vs 81.9 [14.2]; P < .01) and size (0.29 [0.01] vs 0.26 [0.01]; P < .05) of lipid droplets on overexpression in cells. We also observed a reduction of mean (SD) lipid droplets in primary cortical neurons isolated from Cpt1c −/− mice as compared with wild-type mice (1.0 [0.12] vs 0.44 [0.05]; P < .001), suggesting a dominant negative mechanism for the mutation.CONCLUSIONS AND RELEVANCE This study expands the genetics of autosomal dominant HSP and is the first, to our knowledge, to link mutation in CPT1C with a human disease. The association of the CPT1C mutation with changes in lipid droplet biogenesis supports a role for altered lipid-mediated signal transduction in HSP pathogenesis.

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Section: Methodsmentioning

confidence: 99%

Mutation inCPT1CAssociated With Pure Autosomal Dominant Spastic Paraplegia

et al. 2015

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“…The authors performed the experiments under the same conditions as those used in a previous study on the three-dimensional structure of the CPT1A N-terminal domain [15]. They observed that the CPT1C N-terminal domain adopted an inhibitory Nα state that structurally matches that observed for CPT1A.…”

Section: Spatial Structure Of the N-terminal Domainmentioning

confidence: 99%

“…In addition, changes in the malonyl-CoA sensitivity of the enzyme have also been associated with homo-oligomerization [16,17] or heteroassociation with other proteins [18], and they also depend on the composition and curvature of the membrane in which CPT1A lies [15,19].…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

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Carnitine palmitoyltransferase 1C: From cognition to cancer

Casals

Zammit

Herrero

et al. 2016

Progress in Lipid Research

110

101

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Carnitine palmitoyltransferase 1 (CPT1) C was the last member of the CPT1 family of genes to be discovered. CPT1A and CPT1B were identified as the gate-keeper enzymes for the entry of long-chain fatty acids (as carnitine esters) into mitochondria and their further oxidation, and they show differences in their kinetics and tissue expression.Although CPT1C exhibits high sequence similarity to CPT1A and CPT1B, it is specifically expressed in neurons (a cell-type that does not use fatty acids as fuel to any major extent), it is localized in the endoplasmic reticulum of cells, and it has minimal CPT1 catalytic activity with L-carnitine and acyl-CoA esters. The lack of an easily measurable biological activity has hampered attempts to elucidate the cellular and physiological role of CPT1C but has not diminished the interest of the biomedical research community in this CPT1 isoform. The observations that CPT1C binds malonyl-CoA and long-chain acyl-CoA suggest that it is a sensor of lipid metabolism in neurons, where it appears to impact ceramide and triacylglycerol (TAG) metabolism.CPT1C global knock-out mice show a wide range of brain disorders, including impaired cognition and spatial learning, motor deficits, and a deregulation in food intake and energy homeostasis. The first disease-causing CPT1C mutation was recently described in humans, with Cpt1c being identified as the gene causing hereditary spastic paraplegia. The putative role of CPT1C in the regulation of complex-lipid metabolism is supported by the observation that it is highly expressed in certain virulent tumor cells, conferring them resistance to glucose-and oxygen-deprivation. Therefore, CPT1C may be a promising target in the treatment of cancer. Here we review the molecular, biochemical, and structural properties of CPT1C and discuss its potential roles in brain function, and cancer.

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“…(3) Physical changes to OMM properties due to loss of an abundant protein. There is evidence that the fatty acid transport protein CPT1A activity could be regulated by changes in OMM lipid composition and molecular order (Rao et al 2011). Irrespective of the precise mechanism, a function for TSPO in fatty acid metabolism could explain its abundant presence in cells that are active in lipid storage.…”

Section: Tspo As a Regulator Of Lipid Metabolismmentioning

confidence: 99%

Current status and future perspectives: TSPO in steroid neuroendocrinology

Selvaraj

2016

Journal of Endocrinology

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The mitochondrial translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), has received significant attention both as a diagnostic biomarker and as a therapeutic target for different neuronal disease pathologies. Recently, its functional basis believed to be mediating mitochondrial cholesterol import for steroid hormone production has been refuted by studies examining both in vivo and in vitro genetic Tspo-deficient models. As a result, there now exists a fundamental gap in the understanding of TSPO function in the nervous system, and its putative pharmacology in neurosteroid production. In this review, we discuss several recent findings in steroidogenic cells that are in direct contradiction to previous studies, and necessitate a re-examination of the purported role for TSPO in de novo neurosteroid biosynthesis. We critically examine the pharmacological effects of different TSPObinding drugs with particular focus on studies that measure neurosteroid levels. We highlight the basis of key misconceptions regarding TSPO that continue to pervade the literature, and the need for interpretation with caution to avoid negative impacts. We also summarize the emerging perspectives that point to new directions that need to be investigated for understanding the molecular function of TSPO, only after which the true potential of this therapeutic target in medicine may be realized.

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An Environment-dependent Structural Switch Underlies the Regulation of Carnitine Palmitoyltransferase 1A

Cited by 27 publications

References 65 publications

Mutation inCPT1CAssociated With Pure Autosomal Dominant Spastic Paraplegia

Mutation inCPT1CAssociated With Pure Autosomal Dominant Spastic Paraplegia

Carnitine palmitoyltransferase 1C: From cognition to cancer

Current status and future perspectives: TSPO in steroid neuroendocrinology

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