Posttranslational Modification of CLN3 Protein and Its Possible Functional Implication

Michalewski, Martin P.; Kaczmarski, Wojciech; Golabek, Adam A.; Kida, E; Kaczmarski, A.; Wisniewski, Krystyna E.

doi:10.1006/mgme.1999.2818

Cited by 16 publications

(16 citation statements)

References 13 publications

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“…There are three lysosomal localization motifs in the sequence of CLN3: two dileucine sorting motifs in the cytosolic internal loop, and an acidic patch found in the C-terminus [11]–[13]. CLN3 may also be phosphorylated at serine and threonine residues [14]–[16].…”

Section: Introductionmentioning

confidence: 99%

Osmotic Stress Changes the Expression and Subcellular Localization of the Batten Disease Protein CLN3

et al. 2013

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Juvenile CLN3 disease (formerly known as juvenile neuronal ceroid lipofuscinosis) is a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. CLN3 encodes a putative lysosomal transmembrane protein with unknown function. Previous cell culture studies using CLN3-overexpressing vectors and/or anti-CLN3 antibodies with questionable specificity have also localized CLN3 in cellular structures other than lysosomes. Osmoregulation of the mouse Cln3 mRNA level in kidney cells was recently reported. To clarify the subcellular localization of the CLN3 protein and to investigate if human CLN3 expression and localization is affected by osmotic changes we generated a stably transfected BHK (baby hamster kidney) cell line that expresses a moderate level of myc-tagged human CLN3 under the control of the human ubiquitin C promoter. Hyperosmolarity (800 mOsm), achieved by either NaCl/urea or sucrose, dramatically increased the mRNA and protein levels of CLN3 as determined by quantitative real-time PCR and Western blotting. Under isotonic conditions (300 mOsm), human CLN3 was found in a punctate vesicular pattern surrounding the nucleus with prominent Golgi and lysosomal localizations. CLN3-positive early endosomes, late endosomes and cholesterol/sphingolipid-enriched plasma membrane microdomain caveolae were also observed. Increasing the osmolarity of the culture medium to 800 mOsm extended CLN3 distribution away from the perinuclear region and enhanced the lysosomal localization of CLN3. Our results reveal that CLN3 has multiple subcellular localizations within the cell, which, together with its expression, prominently change following osmotic stress. These data suggest that CLN3 is involved in the response and adaptation to cellular stress.

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Section: Introductionmentioning

confidence: 99%

Osmotic Stress Changes the Expression and Subcellular Localization of the Batten Disease Protein CLN3

et al. 2013

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“…CLN3 encodes a 438 amino acid membrane protein that is glycosylated (Ezaki et al, 2003), phosphorylated (Michalewski et al, 1998;Michalewski et al, 1999) and probably farnesylated Pullarkat et al, 1997). It is located in the endosome-lysosome membrane and in neuronal cells is additionally associated with synaptosomes and microvesicles (Ezaki et al, 2003;Haskell et al, 2000;Järvelä et al, 1999;Järvelä et al, 1998;Kyttälä et al, 2003;Luiro et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

btn1, theSchizosaccharomyces pombehomologue of the human Batten disease geneCLN3, regulates vacuole homeostasis

Gachet

Codlin

Hyams

et al. 2005

Journal of Cell Science

100

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“…CLN3 has been shown to undergo phosphorylation when incubated with cAMP-dependent protein kinase, cGMPdependent protein kinase or casein kinase II [21], though the specific residues involved are unknown. Using the ScanPRO-SITE tool, nine potential phosphorylation sites were detected, six on cytoplasmic loops (Ser12, Ser14, Thr19, Thr232, Ser270 and Thr400) and three on lumenal loops (Ser69, Ser74 and Ser86), with the cytoplasmic signatures showing higher conservation on average than those in the lumen.…”

Section: Resultsmentioning

confidence: 99%

The transmembrane topology of Batten disease protein CLN3 determined by consensus computational prediction constrained by experimental data

2008

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The CLN3 gene encodes an integral membrane protein of unknown function. Mutations in CLN3 can cause juvenile neuronal ceroid lipofuscinosis, or Batten disease, an inherited neurodegenerative lysosomal storage disease affecting children. Here, we report a topological study of the CLN3 protein using bioinformatic approaches constrained by experimental data. Our results suggest that CLN3 has a six transmembrane helix topology with cytoplasmic N and C-termini, three large lumenal loops, one of which may contain an amphipathic helix, and one large cytoplasmic loop. Surprisingly, varied topological predictions were made using different subsets of orthologous sequences, highlighting the challenges still remaining for bioinformatics.

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Posttranslational Modification of CLN3 Protein and Its Possible Functional Implication

Cited by 16 publications

References 13 publications

Osmotic Stress Changes the Expression and Subcellular Localization of the Batten Disease Protein CLN3

Osmotic Stress Changes the Expression and Subcellular Localization of the Batten Disease Protein CLN3

btn1, theSchizosaccharomyces pombehomologue of the human Batten disease geneCLN3, regulates vacuole homeostasis

The transmembrane topology of Batten disease protein CLN3 determined by consensus computational prediction constrained by experimental data

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