Analysis of NCL Proteins from an Evolutionary Standpoint

Muzaffar, Neda E.; Pearce, David A.

doi:10.2174/138920208784139573

Cited by 10 publications

(9 citation statements)

References 89 publications

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“…A bioinformatics‐based study classified NCL proteins with respect to sequence and/or function across evolution. According to this analysis, CLN5p and CLN8p are grouped together .…”

Section: Discussionmentioning

confidence: 99%

CLN5 and CLN8 protein association with ceramide synthase: Biochemical and proteomic approaches

et al. 2012

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Four patients with juvenile neuronal ceroid lipofuscinoses, a childhood neurodegenerative disorder that was previously described as CLN9 variant, are reclassified as CLN5 disease. CLN5-deficient (CLN5(-/-) ) fibroblasts demonstrate adhesion defects, increased growth, apoptosis, and decreased levels of ceramide, sphingomyelin, and glycosphingolipids. The CLN8 protein (CLN8p) corrects growth and apoptosis in CLN5(-/-) cells. Related proteins containing a Lag1 motif (CerS1/2/4/5/6) partially corrected these deficits, with CerS1, which is primarily expressed in brain, providing the best complementation, suggesting CLN5p activates CerS1 and may co-immunoprecipitate with it. CLN8p complements CLN5-deficient cells, consolidating the interrelationship of CLN5p/CLN8p, whose potential roles are explored as activators of (dihydro)ceramide synthases. Homozygosity mapping using microarray technology led to identification of CLN5 as the culprit gene in previously classified CLN9-defective cases. Similar to CLN5(-/-) cells, ceramide synthase activity, C16/C18:0/C24:0/C24:1 ceramide species, measured by MS is decreased in CLN8(-/-) cells. Comparison of normal versus CLN5(-/-) cell CerS1-bound proteins by immunoprecipitation, differential gel electrophoresis, and MS revealed absence of γ-actin in CLN5(-/-) cells. The γ-actin gene sequence is normal in CLN5(-/-) derived DNA. The γ-actin-bound proteins, vimentin and histones H2Afz/H3F3A/Hist1H4, were absent from the γ-actin protein complex in CLN5(-/-) cells. The function of CLN5p may require vimentin and the histone proteins to bind γ-actin. Defective binding could explain the CLN5(-/-) cellular phenotype. We explore the role of the CLN5/CLN8 proteins in ceramide species specific sphingolipid de novo synthesis, and suggest that CLN5/CLN8 proteins are more closely related than previously believed.

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“…A bioinformatics‐based study classified NCL proteins with respect to sequence and/or function across evolution. According to this analysis, CLN5p and CLN8p are grouped together .…”

Section: Discussionmentioning

confidence: 99%

CLN5 and CLN8 protein association with ceramide synthase: Biochemical and proteomic approaches

et al. 2012

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“…The CLN3 protein sequence does not display significant similarities to any protein of known function (Muzaffar & Pearce, ). However, some consensus sequence elements within the CLN3 protein allude to its localization, regulation, and function.…”

Section: General Informationmentioning

confidence: 99%

The CLN3 gene and protein: What we know

Mirza¹,

Vainshtein

DiRonza

et al. 2019

Molec Gen & Gen Med

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Background One of the most important steps taken by Beyond Batten Disease Foundation in our quest to cure juvenile Batten (CLN3) disease is to understand the State of the Science. We believe that a strong understanding of where we are in our experimental understanding of the CLN3 gene, its regulation, gene product, protein structure, tissue distribution, biomarker use, and pathological responses to its deficiency, lays the groundwork for determining therapeutic action plans. Objectives To present an unbiased comprehensive reference tool of the experimental understanding of the CLN3 gene and gene product of the same name. Methods BBDF compiled all of the available CLN3 gene and protein data from biological databases, repositories of federally and privately funded projects, patent and trademark offices, science and technology journals, industrial drug and pipeline reports as well as clinical trial reports and with painstaking precision, validated the information together with experts in Batten disease, lysosomal storage disease, lysosome/endosome biology. Results The finished product is an indexed review of the CLN3 gene and protein which is not limited in page size or number of references, references all available primary experiments, and does not draw conclusions for the reader. Conclusions Revisiting the experimental history of a target gene and its product ensures that inaccuracies and contradictions come to light, long‐held beliefs and assumptions continue to be challenged, and information that was previously deemed inconsequential gets a second look. Compiling the information into one manuscript with all appropriate primary references provides quick clues to which studies have been completed under which conditions and what information has been reported. This compendium does not seek to replace original articles or subtopic reviews but provides an historical roadmap to completed works.

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“…Mapping the missense and nonsense mutations on a CLN3 topological model reveals that most of these mutations localize to the luminal side of the transmembrane structure (see red and yellow colored amino acid residues in Figure 2). Of particular note are luminal loop 2, which is also one of the most highly conserved domains across species [36,37] and encompasses the protein sequence encoded by exons 7 and 8 that is excised by the common 1.02-kb deletion mutation, and a predicted amphipathic helix on the luminal face between the 5th and 6th transmembrane helices (Figure 2) [28]. The clustering of most of the missense mutations in these two luminal regions strongly implies that they are critical sites for protein or ligand–substrate binding to mediate CLN3 function.…”

Section: Cln3 Mutations In Jnclmentioning

confidence: 99%

The juvenile Batten disease protein, CLN3, and its role in regulating anterograde and retrograde post-Golgi trafficking

Cotman

Staropoli

2012

Clinical Lipidology

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Loss-of-function mutations in CLN3 are responsible for juvenile-onset neuronal ceroid lipofuscinosis (JNCL), or Batten disease, which is an incurable lysosomal disease that manifests with vision loss, followed by seizures and progressive neurodegeneration, robbing children of motor skills, speech and cognition, and eventually leading to death in the second or third decade of life. Emerging clinical evidence points to JNCL pathology outside of the CNS, including the cardiovascular system. The CLN3 gene encodes an unusual transmembrane protein, CLN3 or battenin, whose elusive function has been the subject of intense study for more than 10 years. Owing to the detailed characterization of a large number of disease models, our knowledge of CLN3 protein function is finally coming into focus. This review will describe the most current understanding of CLN3 structure, function and dysfunction in JNCL.

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Analysis of NCL Proteins from an Evolutionary Standpoint

Cited by 10 publications

References 89 publications

CLN5 and CLN8 protein association with ceramide synthase: Biochemical and proteomic approaches

CLN5 and CLN8 protein association with ceramide synthase: Biochemical and proteomic approaches

The CLN3 gene and protein: What we know

The juvenile Batten disease protein, CLN3, and its role in regulating anterograde and retrograde post-Golgi trafficking

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