The Crystal Structure of Palmitoyl Protein Thioesterase-2 (PPT2) Reveals the Basis for Divergent Substrate Specificities of the Two Lysosomal Thioesterases, PPT1 and PPT2

Calero, Guillermo; Gupta, Praveena; Nonato, Maria Cristina; Tandel, Sagun; Biehl, Edward R.; Hofmann, Sandra L.; Clardy, Jon

doi:10.1074/jbc.m301225200

Cited by 41 publications

(47 citation statements)

References 26 publications

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“…PPT2 knockout mice showed the milder NCL phenotypes such as reduced clasping behavior, enhanced survival rate, and lesser autofluorescent storage material compared to the PPT1 knockout phenotypes. Smaller lipid binding pocket of PPT2 than that of PPT1 revealed by crystal structure [126] could further support the distinct role of PPT2 and may explain the preference of PPT2 thioesterase activity for palmitoyl-CoA over the palmitoylated proteins [124].…”

Section: Other Palmitoyl Thioesterases: Ppt2 and Aptl1mentioning

confidence: 75%

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

Cho

Park

2016

Pharmacological Research

107

108

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Posttranslational modifications of proteins are important regulatory processes endowing the proteins functional complexity. Over the last decade, numerous studies have shed light on the roles of palmitoylation, one of the most common lipid modifications, in various aspects of neuronal functions. Major players regulating palmitoylation are the enzymes that mediate palmitoylation and depalmitoylation which are palmitoyl acyltransferases (PATs) and protein thioesterases, respectively. In this review, we will provide and discuss current understandings on palmitoyation/depalmitoylation control mediated by PATs and/or protein thioesterases for neuronal functions in general and also for Alzheimer's disease in particular, and other neurodegenerative diseases such as Huntington's disease, schizophrenia and intellectual disability.

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Section: Other Palmitoyl Thioesterases: Ppt2 and Aptl1mentioning

confidence: 75%

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

Cho

Park

2016

Pharmacological Research

107

108

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“…Both ␤-galactosidases share lactosylceramide as a substrate, and accumulation of this substrate does not occur in either disorder. Like the two ␤-galactosidases, the two lysosomal thioesterases (PPT1 and PPT2) also have overlapping substrate specificities (9). Both enzymes share palmitoyl CoA as a substrate, whereas palmitoylcysteine is a substrate unique to PPT1, and substrates unique to PPT2 remain to be defined.…”

Section: Discussionmentioning

confidence: 99%

“…The PPT1 or CLN1 gene underlies the most severe form of the disease, and it encodes a thioesterase enzyme that removes palmitate or other fatty acids from cysteine residues in proteins (4)(5)(6). The enzyme encoded by PPT2 is a second lysosomal thioesterase with a substrate specificity that overlaps that of PPT1 (7)(8)(9).…”

mentioning

confidence: 99%

Disruption ofPPT2in mice causes an unusual lysosomal storage disorder with neurovisceral features

Gupta

Soyombo

Shelton

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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The palmitoyl protein thioesterase-2 (PPT2) gene encodes a lysosomal thioesterase homologous to PPT1, which is the enzyme defective in the human disorder called infantile neuronal ceroid lipofuscinosis. In this article, we report that PPT2 deficiency in mice causes an unusual form of neuronal ceroid lipofuscinosis with striking visceral manifestations. All PPT2-deficient mice displayed a neurodegenerative phenotype with spasticity and ataxia by 15 mo. The bone marrow was infiltrated by brightly autofluorescent macrophages and multinucleated giant cells, but interestingly, the macrophages did not have the typical appearance of foam cells commonly associated with other lysosomal storage diseases. Marked splenomegaly caused by extramedullary hematopoiesis was observed. The pancreas was grossly orange to brown as a result of massive storage of lipofuscin pigments in the exocrine (but not islet) cells. Electron microscopy showed that the storage material consisted of multilamellar membrane profiles (''zebra bodies''). In summary, PPT2 deficiency in mice manifests as a neurodegenerative disorder with visceral features. Although PPT2 deficiency has not been described in humans, manifestations would be predicted to include neurodegeneration with bone marrow histiocytosis, visceromegaly, brown pancreas, and linkage to chromosome 6p21.3 in affected families. P almitoyl protein thioesterase (PPT) 2 is a lysosomal thioesterase that is 27% identical to PPT1, a lysosomal enzyme defective in a neurodegenerative disorder called infantile neuronal ceroid lipofuscinosis, or infantile Batten disease (1). The neuronal ceroid lipofuscinosis (NCLs) are a group of neurodegenerative disorders of children characterized by the accumulation of autofluorescent storage material in the brain and other tissues, cognitive and motor deterioration, visual failure, and seizures. Notable is the absence of functionally significant manifestations outside the central nervous system (2, 3). The NCLs are caused by defects in at least eight genes (of which six have been identified), and different forms of the disease have a distinct storage ultrastructure (2). The PPT1 or CLN1 gene underlies the most severe form of the disease, and it encodes a thioesterase enzyme that removes palmitate or other fatty acids from cysteine residues in proteins (4-6). The enzyme encoded by PPT2 is a second lysosomal thioesterase with a substrate specificity that overlaps that of PPT1 (7-9).Recently, we disrupted both PPT1 and PPT2 genes in mice and showed that homozygous PPT1 knockout mice have a neurodegenerative disorder that closely parallels infantile Batten disease (10). Most PPT1 knockout mice are terminal by 10 mo of age. Preliminary analysis of homozygous PPT2 knockout mice at 10 mo had shown the development of scant autofluorescent storage material in the brain and a neurological phenotype in a proportion of the animals. In the current article, we have extended the observation of these PPT2 knockout mice throughout their natural lifespan and analyzed their behavio...

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“…The entrance to the catalytic gorge is flanked by α1 and α10′, a motif common to the active site of other fatty acid ester processing enzymes, including the palmitate protein thioesterases (PPT1 and PPT2). [31][32][33] Adjacent to the gorge opening, Ω1, Ω2, and α10′ form the Z-site, 28,29 a surface ligand binding site that controls the trimer-hexamer equilibrium of the enzyme.…”

Section: Hce1 Structurementioning

confidence: 99%

Multisite Promiscuity in the Processing of Endogenous Substrates by Human Carboxylesterase 1

Bencharit

Edwards

Morton

et al. 2006

Journal of Molecular Biology

126

141

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Human carboxylesterase 1 (hCE1) is a drug and endobiotic-processing serine hydrolase that exhibits relatively broad substrate specificity. It has been implicated in a variety of endogenous cholesterol metabolism pathways including the following apparently disparate reactions: cholesterol ester hydrolysis (CEH), fatty acyl Coenzyme A hydrolysis (FACoAH), acyl-Coenzyme A:cholesterol acyltransfer (ACAT), and fatty acyl ethyl ester synthesis (FAEES). The structural basis for the ability of hCE1 to perform these catalytic actions involving large substrates and products has remained unclear. Here we present four crystal structures of the hCE1 glycoprotein in complexes with the following endogenous substrates or substrate analogues: Coenzyme A, the fatty acid palmitate, and the bile acids cholate and taurocholate. While the active site of hCE1 was known to be promiscuous and capable of interacting with a variety of chemically distinct ligands, these structures reveal that the enzyme contains two additional ligand-binding sites and that each site also exhibits relatively non-specific ligand-binding properties. Using this multisite promiscuity, hCE1 appears structurally capable of assembling several catalytic events depending, apparently, on the physiological state of the cellular environment. These results expand our understanding of enzyme promiscuity and indicate that, in the case of hCE1, multiple non-specific sites are employed to perform distinct catalytic actions.

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The Crystal Structure of Palmitoyl Protein Thioesterase-2 (PPT2) Reveals the Basis for Divergent Substrate Specificities of the Two Lysosomal Thioesterases, PPT1 and PPT2

Cited by 41 publications

References 26 publications

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

Disruption ofPPT2in mice causes an unusual lysosomal storage disorder with neurovisceral features

Multisite Promiscuity in the Processing of Endogenous Substrates by Human Carboxylesterase 1

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