Structural characterization of the regulatory domain of brain carnitine palmitoyltransferase 1.
Structural characterization of the regulatory domain of brain carnitine palmitoyltransferase 1.
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DOI：
10.1002/bip.22396
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发表时间：
2014-04
期刊：
影响因子：
2.9
通讯作者：
Ulmer, Tobias S.
中科院分区：
文献类型：
--
作者：
Samanta, Soma;Situ, Alan J.;Ulmer, Tobias S.
神经元含有肉毒碱棕榈酰转移酶1（CPT 1C）的一种肉毒杆菌特异性亚型，该酶将丙二酰辅酶A与神经酰胺水平偶联，从而有助于全身能量稳态和进食行为。与CPT 1A不同，CPT 1A控制所有组织中长链脂肪酸β-氧化的限速步骤，CPT 1C的生化背景和调控机制尚不清楚。CPT 1酶由N-末端调节结构域和C-末端催化结构域组成，它们被两个跨膜螺旋分开。在CPT 1A中，称为N的调节结构域分别采用抑制和非抑制状态Nα和Nβ，它们与催化结构域的结合不同。为了深入了解CPT 1C的调控机制，我们通过NMR光谱确定了其调控结构域（残基Met 1-Phe 50）的结构。与CPT 1A相关，发现抑制性Nα状态是结构同源物，而非抑制性Nβ状态严重不稳定，表明整体调控发生变化。Nβ的不稳定可能导致CPT 1C相对于CPT 1A的低催化活性，并使其不太可能与催化结构域结合。与CPT 1A催化结构域稳定Nβ类似，CPT 1C的N与另一种蛋白质可能存在非抑制性相互作用。
Neurons contain a mammalian-specific isoform of the enzyme carnitine palmitoyltransferase 1 (CPT1C) that couples malonyl-CoA to ceramide levels thereby contributing to systemic energy homeostasis and feeding behavior. In contrast to CPT1A, which controls the rate-limiting step of long-chain fatty acid β-oxidation in all tissues, the biochemical context and regulatory mechanism of CPT1C are unknown. CPT1 enzymes are comprised of an N-terminal regulatory domain and a C-terminal catalytic domain that are separated by two transmembrane helices. In CPT1A, the regulatory domain, termed N, adopts an inhibitory and non-inhibitory state, Nα and Nβ, respectively, which differ in their association with the catalytic domain. To provide insight into the regulatory mechanism of CPT1C, we have determined the structure of its regulatory domain (residues Met1-Phe50) by NMR spectroscopy. In relation to CPT1A, the inhibitory Nα state was found to be structurally homologues whereas the non-inhibitory Nβ state was severely destabilized, suggesting a change in overall regulation. The destabilization of Nβ may contribute to the low catalytic activity of CPT1C relative to CPT1A and makes its association with the catalytic domain unlikely. In analogy to the stabilization of Nβ by the CPT1A catalytic domain, non-inhibitory interactions of N of CPT1C with another protein may exist.
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影响因子：
4.1
作者：
Fraser, F;Corstorphine, CG;Zammit, VA
通讯作者：
Zammit, VA
DOI：
10.1073/pnas.1103267108
发表时间：
2011-06-07
影响因子：
11.1
作者：
Gao, Su;Zhu, Guangjing;Lopaschuk, Gary D.
通讯作者：
Lopaschuk, Gary D.
Cpt1c 敲除小鼠对高脂饮食引起的葡萄糖不耐受的敏感性增强，涉及肝糖异生作用增强和骨骼肌葡萄糖摄取减少
影响因子：
8.2
作者：
Gao, X. F.;Chen, W.;Wu, D.
通讯作者：
Wu, D.
影响因子：
4.8
作者：
Lopez-Vinas, Eduardo;Bentebibel, Assia;Gomez-Puertas, Paulino
通讯作者：
Gomez-Puertas, Paulino
影响因子：
15
作者：
Hu, JS;Grzesiek, S;Bax, A
通讯作者：
Bax, A