Structural insights into the regulation of human serine palmitoyltransferase complexes.
Structural insights into the regulation of human serine palmitoyltransferase complexes.
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人类丝氨酸棕榈酰转移酶复合物调控的结构性启示。
DOI：
10.1038/s41594-020-00551-9
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发表时间：
2021-03
影响因子：
16.8
通讯作者：
Lee, Chia-Hsueh
中科院分区：
文献类型：
--
作者：
Wang, Yingdi;Niu, Yiming;Zhang, Zhe;Gable, Kenneth;Gupta, Sita D.;Somashekarappa, Niranjanakumari;Han, Gongshe;Zhao, Hongtu;Myasnikov, Alexander G.;Kalathur, Ravi C.;Dunn, Teresa M.;Lee, Chia-Hsueh
鞘脂是真核生物膜中必不可少的脂质。在人体中，鞘磷脂合成的第一步和限速步骤由丝氨酸棕榈酰基转移酶整体复合体催化，该复合体由催化元件（SPTLC1 和 SPTLC2）和调节元件（ssSPTa 和 ORMDL3）组成。然而，该复合体的组装、底物处理和调控尚不清楚。在这里，我们以 2.6-3.4 Å 的分辨率展示了人类丝氨酸棕榈酰基转移酶全复合体在不同功能状态下的八个冷冻电镜结构。这些结构不仅揭示了催化元件如何识别底物，还揭示了调控元件如何调节底物结合隧道以控制酶的活性：ssSPTa 与 SPTLC2 结合并形成隧道以确定底物的特异性。ORMDL3 阻断了隧道，并通过其 N 端与底物结合竞争。这些发现从机理上揭示了丝氨酸棕榈酰基转移酶复合物所控制的鞘脂生物生成过程。
催化鞘脂合成限速步骤的酶复合物的冷冻电镜结构揭示了底物识别和调节亚基的调节机制。
Sphingolipids are essential lipids in eukaryotic membranes. In humans, the first and rate-limiting step of sphingolipid synthesis is catalyzed by the serine palmitoyltransferase holocomplex, which consists of catalytic components (SPTLC1 and SPTLC2), and regulatory components (ssSPTa and ORMDL3). However, the assembly, substrate processing, and regulation of the complex are unclear. Here we present eight cryo-electron microscopy structures of the human serine palmitoyltransferase holocomplex in various functional states at 2.6–3.4 Å resolution. The structures reveal not only how catalytic components recognize the substrate, but also how regulatory components modulate the substrate binding tunnel to control enzyme activity: ssSPTa engages SPTLC2 and shapes the tunnel to determine substrate specificity. ORMDL3 blocks the tunnel and competes with substrate binding through its N-terminus. These findings provide mechanistic insights into sphingolipid biogenesis governed by the serine palmitoyltransferase complex. Cryo-EM structures of the enzyme complexes catalyzing the rate-limiting step in sphingolipid synthesis reveal mechanisms of substrate recognition and modulation by regulatory subunits.
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DOI：
10.1038/nrm.2017.107
发表时间：
2018-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Hannun YA;Obeid LM
通讯作者：
Obeid LM
DOI：
10.1073/pnas.0811269106
发表时间：
2009-05-19
影响因子：
11.1
作者：
Han, Gongshe;Gupta, Sita D.;Dunn, Teresa M.
通讯作者：
Dunn, Teresa M.
影响因子：
7.3
作者：
Genin, Michael J.;Valcarcel, Isabel C. Gonzalez;Brozinick, Joseph T.
通讯作者：
Brozinick, Joseph T.
影响因子：
4.8
作者：
Gupta, Sita D.;Gable, Kenneth;Harmon, Jeffrey M.
通讯作者：
Harmon, Jeffrey M.
影响因子：
3.5
作者：
Bode, Heiko;Bourquin, Florence;Hornemann, Thorsten
通讯作者：
Hornemann, Thorsten