Cln5 represents a new type of cysteine-based S-depalmitoylase linked to neurodegeneration.
Cln5 represents a new type of cysteine-based S-depalmitoylase linked to neurodegeneration.
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CLN5代表一种与神经变性相关的新型基于半胱氨酸的S-脱甲莫酰基。
DOI：
10.1126/sciadv.abj8633
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发表时间：
2022-04-15
期刊：
影响因子：
13.6
通讯作者：
Steinfeld, Robert
中科院分区：
文献类型：
--
作者：
Luebben, Anna, V;Bender, Daniel;Becker, Stefan;Crowther, Lisa M.;Erven, Ilka;Hofmann, Kay;Soeding, Johannes;Klemp, Henry;Bellotti, Cristina;Stauble, Andreas;Qiu, Tian;Kathayat, Rahul S.;Dickinson, Bryan C.;Gaertner, Jutta;Sheldrick, George M.;Kraetzner, Ralph;Steinfeld, Robert
CLN5基因变异与儿童神经退行性变和阿尔茨海默病有关；然而，蜡样脂褐素沉积症神经元蛋白5(CLN5)的分子功能尚不清楚。我们解析了CLN5的晶体结构，并确定了与类木瓜酶N1pC/P60超家族成员的催化结构域同源的区域。然而，我们没有观察到CLN5的蛋白酶活性；相反，我们发现CLN5及其结构上相关的PPPDE1和PPPDE2具有有效的半胱氨酸棕榈酰硫酯酶(S脱氨基)活性。突变分析表明，预测的催化残基组氨酸-166和半胱氨酸-280是CLN5硫代酯酶活性的关键，揭示了一种新的基于半胱氨酸的S脱氨酶催化机理。最后，我们发现CLN5基因缺陷的神经前体细胞的硫酯酶活性降低，证实了CLN5在调节S脱氨酶水平中的活细胞功能。我们的结果为了解CLN5的功能提供了新的视角，强调了S脱氨酶在神经元动态平衡中的重要性，并揭示了N1pC/P60超家族蛋白的一种新的、意想不到的酶功能。CLN5结构揭示了N1pC/P60蛋白中硫代酯酶的活性，强调了S脱醛核苷化在神经退行性变中的作用。
Genetic CLN5 variants are associated with childhood neurodegeneration and Alzheimer’s disease; however, the molecular function of ceroid lipofuscinosis neuronal protein 5 (Cln5) is unknown. We solved the Cln5 crystal structure and identified a region homologous to the catalytic domain of members of the N1pC/P60 superfamily of papain-like enzymes. However, we observed no protease activity for Cln5; and instead, we discovered that Cln5 and structurally related PPPDE1 and PPPDE2 have efficient cysteine palmitoyl thioesterase (S-depalmitoylation) activity using fluorescent substrates. Mutational analysis revealed that the predicted catalytic residues histidine-166 and cysteine-280 are critical for Cln5 thioesterase activity, uncovering a new cysteine-based catalytic mechanism for S-depalmitoylation enzymes. Last, we found that Cln5-deficient neuronal progenitor cells showed reduced thioesterase activity, confirming live cell function of Cln5 in setting S-depalmitoylation levels. Our results provide new insight into the function of Cln5, emphasize the importance of S-depalmitoylation in neuronal homeostasis, and disclose a new, unexpected enzymatic function for the N1pC/P60 superfamily of proteins. Cln5 structure reveals thioesterase activity among N1pC/P60 proteins, stressing the role of S-depalmitoylation in neurodegeneration.
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影响因子：
5.5
作者：
Basak I;Hansen RA;Ward ME;Hughes SM
通讯作者：
Hughes SM
DOI：
10.1073/pnas.1708568114
发表时间：
2017-11-07
影响因子：
11.1
作者：
Andrew, Robert J.;Fernandez, Celia G.;Thinakaran, Gopal
通讯作者：
Thinakaran, Gopal
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
3.9
作者：
Kousi, Maria;Lehesjoki, Anna-Elina;Mole, Sara E.
通讯作者：
Mole, Sara E.