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CLN6’s luminal tail-mediated functional interference between CLN6 mutants as a novel pathomechanism for the neuronal ceroid lipofuscinoses
https://tokushima-u.repo.nii.ac.jp/records/2009102
https://tokushima-u.repo.nii.ac.jp/records/2009102e93f84d9-0c3e-42e7-85b6-3b9ddce6861a
| 名前 / ファイル | ライセンス | アクション |
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biomedres_42_4_129.pdf (2.58 MB)
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| Item type | 文献 / Documents(1) | |||||||||||||||||||||||||||||
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| 公開日 | 2021-08-24 | |||||||||||||||||||||||||||||
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| アクセス権 | open access | |||||||||||||||||||||||||||||
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| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||||||||||||||||||||||||||
| 資源タイプ | journal article | |||||||||||||||||||||||||||||
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| 関連識別子 | https://doi.org/10.2220/biomedres.42.129 | |||||||||||||||||||||||||||||
| 関連名称 | 10.2220/biomedres.42.129 | |||||||||||||||||||||||||||||
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| 出版タイプ | VoR | |||||||||||||||||||||||||||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||||||||||||||||||||||||||
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| タイトル | CLN6’s luminal tail-mediated functional interference between CLN6 mutants as a novel pathomechanism for the neuronal ceroid lipofuscinoses | |||||||||||||||||||||||||||||
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| その他のタイトル | Interference of CLN6 mutants | |||||||||||||||||||||||||||||
| 著者 |
シロ, ユウキ
× シロ, ユウキ
× ヤマシタ, アリサ
× ワタナベ, カナ
× 山﨑, 哲男
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| 内容記述 | CLN6 (Ceroid Lipofuscinosis, Neuronal, 6) is a 311-amino acid protein spanning the endoplasmic reticulum membrane. Mutations in CLN6 are linked to CLN6 disease, a hereditary neurodegenerative disorder categorized into the neuronal ceroid lipofuscinoses. CLN6 disease is an autosomal recessive disorder and individuals affected with this disease have two identical (homozygous) or two distinct (compound heterozygous) CLN6 mutant alleles. Little has been known about CLN6’s physiological roles and the disease mechanism. We recently found that CLN6 prevents protein aggregate formation, pointing to impaired CLN6’s anti-aggregate activity as a cause for the disease. To comprehensively understand the pathomechanism, overall anti-aggregate activity derived from two different CLN6 mutants needs to be investigated, considering patients compound heterozygous for CLN6 alleles. We focused on mutant combinations involving the S132CfsX18 (132fsX) prematurely terminated protein, produced from the most frequent mutation in CLN6. The 132fsX mutant nullified anti-aggregate activity of the P299L CLN6 missense mutant but not of wild-type CLN6. Wild-type CLN6’s resistance to the 132fsX mutant was abolished by replacement of amino acids 297–301, including Pro297 and Pro299, with five alanine residues. Given that removal of CLN6’s C-terminal fifteen amino acids 297–311 (luminal tail) did not affect the resistance, we suggested that CLN6’s luminal tail, when unleashed from Pro297/299-mediated conformational constraints, is improperly positioned by the 132fsX mutant, thereby blocking the induction of anti- aggregate activity. We here reveal a novel mechanism for dissipating CLN6 mutants’ residual functions, providing an explanation for the compound heterozygosity-driven pathogenesis. | |||||||||||||||||||||||||||||
| 書誌情報 |
en : Biomedical Research 巻 42, 号 4, p. 129-138, 発行日 2021-08-12 |
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| 収録物識別子タイプ | ISSN | |||||||||||||||||||||||||||||
| 収録物識別子 | 1880313X | |||||||||||||||||||||||||||||
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| 出版者 | Biomedical Research Press | |||||||||||||||||||||||||||||
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| 識別子 | 379112 | |||||||||||||||||||||||||||||
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| 言語 | eng | |||||||||||||||||||||||||||||
