ArticleThe Journal of biological chemistry2009
Crystal structure and autoactivation pathway of the precursor form of human tripeptidyl-peptidase 1, the enzyme deficient in late infantile ceroid lipofuscinosis.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 65 citations in OpenAlex.
- Bi-allelic TPP1 variants in neuronal ceroid lipofuscinosis 2: clinical findings from an Iranian cohort of 20 patients, founder effect, and in silico analyses.Human genetics · 2026Article
- Systematic discovery of disease-modifying targets by prediction from knowledge graph-based AI model and experimental validation: Parkinson's disease case.Computational and structural biotechnology journal · 2026Article
- GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice.JCI insight · 2025Article
- Benchmarking Nanopore Sequencing for CLN2 (TPP1) Mutation Detection: Integrating Rapid Genomics and Orthogonal Validation for Precision Diagnostics.International journal of molecular sciences · 2025Article
- Structural Catalytic Core in Subtilisin-like Proteins and Its Comparison to Trypsin-like Serine Proteases and Alpha/Beta-Hydrolases.International journal of molecular sciences · 2024Review
- A computational approach to analyzing the functional and structural impacts of Tripeptidyl-Peptidase 1 missense mutations in neuronal ceroid lipofuscinosis.Metabolic brain disease · 2024Article
- Neuroprotective effects of gemfibrozil in neurological disorders: Focus on inflammation and molecular mechanisms.CNS neuroscience & therapeutics · 2024Review
- Hidden Relationships betweenInternational journal of molecular sciences · 2022Review
- Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression.Journal of neuroinflammation · 2021Article
- Exploiting the diphtheria toxin internalization receptor enhances delivery of proteins to lysosomes for enzyme replacement therapy.Science advances · 2020Article
- Intravitreal enzyme replacement preserves retinal structure and function in canine CLN2 neuronal ceroid lipofuscinosis.Experimental eye research · 2020Article
- Lysosomal protein thermal stability does not correlate with cellular half-life: global observations and a case study of tripeptidyl-peptidase 1.The Biochemical journal · 2020Article
- Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses.Molecular neurodegeneration · 2019Review
- Marginal protein stability drives subcellular proteome isoelectric point.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- N-Gemini peptides: cytosolic protease resistance via N-terminal dimerization of unstructured peptides.Chemical communications (Cambridge, England) · 2017Article
- A tripeptidyl peptidase 1 is a binding partner of the Golgi pH regulator (GPHR) inDisease models & mechanisms · 2017Article
- Competing targets of microRNA-608 affect anxiety and hypertension.Human molecular genetics · 2014Article
- Effective intravenous therapy for neurodegenerative disease with a therapeutic enzyme and a peptide that mediates delivery to the brain.Molecular therapy : the journal of the American Society of Gene Therapy · 2014Article
- Potential pitfalls and solutions for use of fluorescent fusion proteins to study the lysosome.PloS one · 2014Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
Late infantile neuronal ceroid lipofuscinosis is a fatal childhood neurological disorder caused by a deficiency in the lysosomal protease tripeptidyl-peptidase 1 (TPP1). TPP1 represents the only known mammalian member of the S53 family of serine proteases, a group characterized by a subtilisin-like fold, a Ser-Glu-Asp catalytic triad, and an acidic pH optimum. TPP1 is synthesized as an inactive proenzyme (pro-TPP1) that is proteolytically processed into the active enzyme after exposure to low pH in vitro or targeting to the lysosome in vivo. In this study, we describe an endoglycosidase H-deglycosylated form of TPP1 containing four Asn-linked N-acetylglucosamines that is indistinguishable from fully glycosylated TPP1 in terms of autocatalytic processing of the proform and enzymatic properties of the mature protease. The crystal structure of deglycosylated pro-TPP1 was determined at 1.85 angstroms resolution. A large 151-residue C-shaped prodomain makes extensive contacts as it wraps around the surface of the catalytic domain with the two domains connected by a 24-residue flexible linker that passes through the substrate-binding groove. The proenzyme structure reveals suboptimal catalytic triad geometry with its propiece linker partially blocking the substrate-binding site, which together serve to prevent premature activation of the protease. Finally, we have identified numerous processing intermediates and propose a structural model that explains the pathway for TPP1 activation in vitro. These data provide new insights into TPP1 function and represent a valuable resource for constructing improved TPP1 variants for treatment of late infantile neuronal ceroid lipofuscinosis.
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