Different Patterns of Hydrophobic Protein Storage in Different Forms of Neuronal Ceroid Lipofuscinosis (NCL, Batten Disease)

Palmer, David N.; Jolly, R. D.; Mil, H. C. van; Tyynelä, Jaana; Westlake, V. J.

doi:10.1055/s-2007-973666

Cited by 67 publications

(46 citation statements)

References 4 publications

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“…The specific pathophysiological processes that both lead to and result from this accumulation are not well understood, and this hydrophobic membrane protein has been identified as a prominent component in the storage material in many other NCLs (19). If subunit c is directly degraded by TPP I, the results presented here indicate that it would represent only an average substrate, with a predicted relative substrate specificity constant of 1.8 ϫ 10 Ϫ5 based on its N-terminal sequence DIDTA (Table 4; 1.8 ϫ 10 Ϫ5 ϭ 0.031 ϫ 0.18 ϫ 0.023 ϫ 0.26 ϫ 0.56).…”

Section: Discussionmentioning

confidence: 99%

“…However, this extremely hydrophobic protein also accumulates in a number of different other NCLs (17)(18)(19)(20)(21)(22). Without detailed understanding of TPP I substrate specificity and the combined actions of other lysosomal proteinases, it remains difficult to distinguish whether subunit c accumulation in LINCL is a primary or secondary effect of TPP I deficiency.…”

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confidence: 99%

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Determination of the Substrate Specificity of Tripeptidyl-peptidase I Using Combinatorial Peptide Libraries and Development of Improved Fluorogenic Substrates

Tian¹,

Sohár²,

Taylor

et al. 2006

Journal of Biological Chemistry

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Classical late-infantile neuronal ceroid lipofuscinosis is a fatal neurodegenerative disease caused by mutations in CLN2, the gene encoding the lysosomal protease tripeptidyl-peptidase I (TPP I). The natural substrates for TPP I and the pathophysiological processes associated with lysosomal storage and disease progression are not well understood. Detailed characterization of TPP I substrate specificity should provide insights into these issues and also aid in the development of improved clinical and biochemical assays. To this end, we constructed fluorogenic and standard combinatorial peptide libraries and analyzed them using fluorescence and mass spectrometry-based activity assays. The fluorogenic group 7-amino-4-carbamoylmethylcoumarin was incorporated into a series of 7-amino-4-carbamoylmethylcoumarin tripeptide libraries using a design strategy that allowed systematic evaluation of the P1, P2, and P3 positions. TPP I digestion of these substrates liberates the fluorescence group and results in a large increase in fluorescence that can be used to calculate kinetic parameters and to derive the substrate specificity constant k cat /K M . In addition, we implemented a mass spectrometry-based assay to measure the hydrolysis of individual peptides in peptide pools and thus expand the scope of the analysis. Nonfluorogenic tetrapeptide and pentapeptide libraries were synthesized and analyzed to evaluate P1 and P2 residues. Together, this analysis allowed us to predict the relative specificity of TPP I toward a wide range of potential biological substrates. In addition, we evaluated a variety of new fluorogenic peptides with a P3 Arg residue, and we demonstrated their superiority compared with the widely used substrate Ala-Ala-Phe-AMC for selectively measuring TPP I activity in biological specimens.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Determination of the Substrate Specificity of Tripeptidyl-peptidase I Using Combinatorial Peptide Libraries and Development of Improved Fluorogenic Substrates

Tian¹,

Sohár²,

Taylor

et al. 2006

Journal of Biological Chemistry

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“…In vitro, TPP I cleaved peptide hormones such as angiotensin II, glucagon (4), substance P (17), angiotensin III, and neuromedin B (16) as well as synthetic amyloid-␤ peptide 1-42 and 1-28 (17) and most probably collagen (4) and subunit c of mitochondrial ATP synthase (17,18), a proteolipid that accumulates in all types of neuronal ceroid lipofuscinoses except for the infantile form (20). The activity of TPP I can be inhibited efficiently by the tripeptide analogue of the substrate Ala-Ala-Phe-chloromethylketone (AAF-CMK) (3,4,17,21).…”

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confidence: 99%

Biosynthesis, Glycosylation, and Enzymatic Processingin Vivo of Human Tripeptidyl-peptidase I

Golabek

Kida

Walus

et al. 2003

Journal of Biological Chemistry

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Human tripeptidyl-peptidase I (TPP I, CLN2 protein) is a lysosomal serine protease that removes tripeptides from the free N termini of small polypeptides and also shows a minor endoprotease activity. Due to various naturally occurring mutations, an inherited deficiency of TPP I activity causes a fatal lysosomal storage disorder, classic late infantile neuronal ceroid lipofuscinosis (CLN2). In the present study, we analyzed biosynthesis, glycosylation, transport, and proteolytic processing of this enzyme in stably transfected Chinese hamster ovary cells as well as maturation of the endocytosed proenzyme in CLN2 lymphoblasts, fibroblasts, and N2a cells. Human TPP I was initially identified as a single precursor polypeptide of ϳ68 kDa, which, within a few hours, was converted to the mature enzyme of ϳ48 kDa. Degradation of polypeptides requires the collective action of various endo-and exopeptidases, finally releasing free amino acids and dipeptides reused in the cell cytoplasm according to the metabolic needs of the cell. Two tripeptidyl peptidases identified to date in mammalian cells sequentially cleave tripeptides from the N termini of oligopeptides: tripeptidyl peptidase I (TPP I, 1 CLN2 protein) and tripeptidyl peptidase II (TPP II) (for a recent review, see Ref.

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“…Histochemically, lysosomal acid phosphatase activity is associated with the storage material. Immunohistochemcially, a few extremely hydrophobic proteins are detected in the lipopigment storage material; these include subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins (SAPs or saposins) A and D [39][40][41][42][43][44][45].…”

Section: Ultrastructural Patternsmentioning

confidence: 99%

Neuronal ceroid-lipofuscinoses

Rakheja

Bennett

2018

TRD

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Abstract. The neuronal ceroid-lipofuscinoses (NCLs) are a group of recessively inherited diseases characterized by progressive neuronal loss, accumulation of intracellular lipofuscin-like autofluorescent storage material with distinctive ultrastructural features, and clinical signs and symptoms of progressive neurodegeneration. Initially classified by the age of onset of clinical signs and symptoms as well as the ultrastructural morphology of the storage material, the growing family of NCLs can now also be biologically classified by their underlying genetic defects. For a few NCLs, we now understand the functions of the proteins encoded by the NCL genes, which has enabled refining of the diagnostic algorithms and ignited hopes for finding effective treatments in the future. Ongoing research into understanding the functions of the remainder of the NCL proteins as well as continuing advancements in technology (such as massively-parallel gene sequencing) has and will continue to inform the clinical approach, diagnostic algorithms, and treatment strategies.

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Different Patterns of Hydrophobic Protein Storage in Different Forms of Neuronal Ceroid Lipofuscinosis (NCL, Batten Disease)

Cited by 67 publications

References 4 publications

Determination of the Substrate Specificity of Tripeptidyl-peptidase I Using Combinatorial Peptide Libraries and Development of Improved Fluorogenic Substrates

Determination of the Substrate Specificity of Tripeptidyl-peptidase I Using Combinatorial Peptide Libraries and Development of Improved Fluorogenic Substrates

Biosynthesis, Glycosylation, and Enzymatic Processingin Vivo of Human Tripeptidyl-peptidase I

Neuronal ceroid-lipofuscinoses

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