Cryo-EM reveals mechanistic insights into lipid-facilitated polyamine export by human ATP13A2.
Cryo-EM reveals mechanistic insights into lipid-facilitated polyamine export by human ATP13A2.
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冷冻电镜揭示了人类ATP13A2借助脂质促进多胺输出的机制见解。
DOI：
10.1016/j.molcel.2021.11.001
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发表时间：
2021-12-02
期刊：
影响因子：
16
通讯作者：
Nureki O
中科院分区：
文献类型：
--
作者：
Tomita A;Daiho T;Kusakizako T;Yamashita K;Ogasawara S;Murata T;Nishizawa T;Nureki O
胞质多胺通过螯合有毒金属阳离子、调节转录活性和保护DNA来维持细胞内稳态。ATP 13 A2是一种溶酶体多胺输出蛋白，负责将多胺释放到细胞质中，其功能障碍与阿尔茨海默病和其他神经退行性疾病有关。ATP 13 A2属于P型ATP酶家族的P5亚家族，但其机制尚不清楚。在这里，我们报告的冷冻电镜（cryo-EM）结构的人ATP 13 A2在四种不同的条件下，揭示了多胺结合和去磷酸化之间的结构耦合。多胺结合在管腔通道处，并通过许多静电和p-阳离子相互作用被识别，这解释了其广泛的特异性。独特的N-末端结构域锚定在脂质膜上以稳定E2 P构象，从而加速E1 P到E2 P的转变。这些发现揭示了P5 B ATP酶的独特机制，从而为通过激活ATP 13 A2进行神经保护治疗铺平了道路。Tomita等人报告了ATP 13 A2在E1-ATP、E1 P-ADP、SPM结合的E2 P（E2 P（SPM））和SPM结合的E2 Pi（E2 Pi（SPM））状态下的冷冻-EM结构。这些结构结合分子动力学模拟揭示了ATP 13 A2对多胺的转运机制。
The cytoplasmic polyamine maintains cellular homeostasis by chelating toxic metal cations, regulating transcriptional activity, and protecting DNA. ATP13A2 was identified as a lysosomal polyamine exporter responsible for polyamine release into the cytosol, and its dysfunction is associated with Alzheimer’s disease and other neural degradation diseases. ATP13A2 belongs to the P5 subfamily of the P-type ATPase family, but its mechanisms remain unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human ATP13A2 under four different conditions, revealing the structural coupling between the polyamine binding and the dephosphorylation. Polyamine is bound at the luminal tunnel and recognized through numerous electrostatic and p-cation interactions, explaining its broad specificity. The unique N-terminal domain is anchored to the lipid membrane to stabilize the E2P conformation, thereby accelerating the E1P-to-E2P transition. These findings reveal the distinct mechanism of P5B ATPases, thereby paving the way for neuroprotective therapy by activating ATP13A2. Tomita et al. report the cryo-EM structure of ATP13A2 in E1-ATP, E1P-ADP, SPM-bound E2P (E2P(SPM)), and SPM-bound E2Pi (E2Pi(SPM)) states. These structures together with molecular dynamics simulation reveal the transport mechanism of polyamine by ATP13A2.
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影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
影响因子：
3.7
作者：
Kanemura A;Yoshikawa Y;Fukuda W;Tsumoto K;Kenmotsu T;Yoshikawa K
通讯作者：
Yoshikawa K
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
影响因子：
4.4
作者：
FELLER, SE;ZHANG, YH;BROOKS, BR
通讯作者：
BROOKS, BR
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD