Nature Communications ：人磷酸果糖激酶-1变构调控的结构基础-动脉网

Nature Communications ：Structural basis for allosteric regulation of human phosphofructokinase-1

Nature 等信源发布 2024-08-25 21:16

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AbstractPhosphofructokinase-1 (PFK1) catalyzes the rate-limiting step of glycolysis, committing glucose to conversion into cellular energy. PFK1 is highly regulated to respond to the changing energy needs of the cell. In bacteria, the structural basis of PFK1 regulation is a textbook example of allostery; molecular signals of low and high cellular energy promote transition between an active R-state and inactive T-state conformation, respectively.

磷酸果糖激酶-1（PFK1）催化糖酵解的限速步骤，使葡萄糖转化为细胞能量。PFK1受到高度调节，以响应细胞不断变化的能量需求。在细菌中，PFK1调节的结构基础是变构的教科书例子；低和高细胞能量的分子信号分别促进活性R态和非活性T态构象之间的转变。

Little is known, however, about the structural basis for regulation of eukaryotic PFK1. Here, we determine structures of the human liver isoform of PFK1 (PFKL) in the R- and T-state by cryoEM, providing insight into eukaryotic PFK1 allosteric regulatory mechanisms. The T-state structure reveals conformational differences between the bacterial and eukaryotic enzyme, the mechanisms of allosteric inhibition by ATP binding at multiple sites, and an autoinhibitory role of the C-terminus in stabilizing the T-state.

然而，关于真核PFK1调控的结构基础知之甚少。在这里，我们通过cryoEM确定了R和T状态下PFK1（PFKL）的人肝同工型的结构，为真核PFK1变构调节机制提供了见识。T态结构揭示了细菌和真核酶之间的构象差异，ATP在多个位点结合的变构抑制机制，以及C末端在稳定T态中的自抑制作用。

We also determine structures of PFKL filaments that define the mechanism of higher-order assembly and demonstrate that these structures are necessary for higher-order assembly of PFKL in cells..

我们还确定了PFKL细丝的结构，这些结构定义了高阶组装的机制，并证明了这些结构对于细胞中PFKL的高阶组装是必需的。。

IntroductionGlycolysis is an ancient, highly-conserved metabolic pathway for the extraction of energy from sugars. During glycolysis, glucose is metabolized to produce energy in the form of ATP, the essential cofactor NADH, as well as other biosynthetic precursors to support cellular functions. The first committed step of glycolysis is catalyzed by phosphofructokinase-1 (PFK1), which converts fructose 6-phosphate (F6P) to fructose 1,6-bisphosphate (F1,6BP), consuming one molecule of ATP in the process.

引言糖酵解是一种古老的，高度保守的代谢途径，用于从糖中提取能量。在糖酵解过程中，葡萄糖被代谢产生ATP形式的能量，ATP是必需的辅助因子NADH，以及支持细胞功能的其他生物合成前体。糖酵解的第一步是由磷酸果糖激酶-1（PFK1）催化的，它将果糖6-磷酸（F6P）转化为果糖1,6-二磷酸（F1,6BP），在此过程中消耗一分子ATP。

Given this central role as the gatekeeper of glycolysis, PFK1 is heavily regulated by the energy state of the cell; PFK1 is activated by signals of low cellular energy, such as AMP and ADP, and inhibited by signals of high cellular energy, such as ATP and citrate.The structural basis for PFK1 regulation is best described for the bacterial enzyme1,2,3.

鉴于这种作为糖酵解守门人的核心作用，PFK1受到细胞能量状态的严重调节；PFK1被低细胞能量的信号激活，例如AMP和ADP，并被高细胞能量的信号抑制，例如ATP和柠檬酸盐。PFK1调节的结构基础最好描述为细菌酶1,2,3。

Bacterial PFK1 is a D2-symmetric homotetramer with four active sites, each formed at an interface between two monomers. The enzyme transitions between an active R-state conformation, promoted by binding to F6P and allosteric activators, and an inactive T-state conformation, observed in the absence of F6P and upon binding to allosteric inhibitors.

细菌PFK1是具有四个活性位点的D2对称同四聚体，每个活性位点形成于两个单体之间的界面。该酶在通过与F6P和变构激活剂结合而促进的活性R态构象与在不存在F6P和与变构抑制剂结合时观察到的无活性T态构象之间转变。

The R-state to T-state transition involves a rotation between essentially rigid dimers and rearrangement of active site residues, which together function to disrupt the F6P binding pocket2.The PFK1 catalytic domain architecture is conserved in eukaryotes. However, eukaryotic PFK1 has an additional regulatory domain, which arose from gene duplication, tandem fusion, and evolution of the ancestral prokaryotic catalytic domain4,5,6.

R态到T态的转变涉及基本刚性二聚体之间的旋转和活性位点残基的重排，它们共同起破坏F6P结合口袋2的作用。PFK1催化结构域在真核生物中是保守的。然而，真核生物PFK1具有另外的调节结构域，其产生于基因复制，串联融合和祖先原核催化结构域的进化4,5,6。

The resulting eukaryotic PFK1 monomer corresponds to the bacterial dimer that rotates as an essentially rigid body during the R- to T-state transition. Gen.

所得的真核PFK1单体对应于细菌二聚体，其在R到T状态转变期间作为基本刚体旋转。发电机。

Data availability

数据可用性

Cryo-EM structures and atomic models have been deposited in the Electron Microscopy Data Bank (EMDB) and Protein Data Bank (PDB), respectively, with the following accession codes: EMD-43747, PDB: 8W2G (R-state PFKL tetramer); EMD-43749, PDB: 8W2I (R-state PFKL filament); EMD-43748, PDB: 8W2H (T-state PFKL tetramer); EMD-43750, PDB: 8W2J (T-state PFKL filament).

低温电磁结构和原子模型已分别保存在电子显微镜数据库（EMDB）和蛋白质数据库（PDB）中，登录号如下：EMD-43747，PDB:8W2G（R态PFKL四聚体）；EMD-43749，PDB:8W2I（R态PFKL灯丝）；EMD-43748，PDB:8W2H（T态PFKL四聚体）；EMD-43750，PDB:8W2J（T态PFKL灯丝）。

MD simulation input files and final geometries, as well as node degeneracies from network path analysis, are available on Zenodo (https://doi.org/10.5281/zenodo.12168317). The reference structure used in this work is 4XYJ. Source Data are provided as a Source Data file. Source data are provided with this paper..

Zenodo上提供了MD模拟输入文件和最终几何形状，以及网络路径分析中的节点退化(https://doi.org/10.5281/zenodo.12168317)。这项工作中使用的参考结构是4XYJ。源数据作为源数据文件提供。本文提供了源数据。。

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Download referencesAcknowledgementsWe are grateful to the Arnold and Mabel Beckman Cryo-EM Center at the University of Washington for the use of electron microscopes. This work was supported by the National Institutes of Health (1R35GM149542 and S10OD023476 to J.M.K.). S.T. was supported by the Czech Science Foundation (grant no.

下载参考文献致谢我们感谢华盛顿大学阿诺德和梅布尔·贝克曼冷冻电镜中心使用电子显微镜。这项工作得到了美国国立卫生研究院的支持（J.M.K.的1R35GM149542和S10OD023476）。S、 T.得到了捷克科学基金会的支持（批准号：。

23-06437S). B.A.W was supported by West Virginia University Start-up funding and Visual Sciences CoBRE project leader funding (P20GM144230). The authors would like to thank Ms. Katelyn Frock for her technical assistance.Author informationAuthors and AffiliationsDepartment of Biochemistry, University of Washington, Seattle, WA, USAEric M.

。B、 A.W得到了西弗吉尼亚大学创业基金和视觉科学CoBRE项目领导基金（P20GM144230）的支持。作者要感谢Katelyn Frock女士的技术援助。作者信息作者和附属机构华盛顿大学生物化学系，华盛顿州西雅图，USAEric M。

Lynch, Lauren Salay & Justin M. KollmanDepartment of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV, USAHeather Hansen, Madison Cooper & Bradley A. WebbDepartment of Computational Chemistry, J. Heyrovsky Institute of Physical Chemistry, Czech Academy of Sciences, Prague, Czech RepublicStepan TimrAuthorsEric M.

林奇（Lynch），劳伦·萨利（Lauren Salay）和贾斯汀·科尔曼（Justin M.KollmanDepartment of Biochemistry and Molecular Medicine），西弗吉尼亚大学（West Virginia University），莫根敦（Morgantown），威斯康星州（WV），美国希瑟·汉森（USAHeather Hansen），麦迪逊·库珀（Madison Cooper）和布拉德利（Bradley A.Webb）计算化学系，捷克共和国布拉。

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PubMed Google ScholarContributionsE.M.L., H.H., L.S., M.C., S.T., and B.A.W. performed experiments and analyzed data. E.M.L, L.S., S.T., B.A.W., and J.M.K. prepared and edited the manuscript. S.T., B.A.W., and J.M.K. supervised the work.Corresponding authorsCorrespondence to

PubMed谷歌学术贡献。M、 L.，H.H.，L.S.，M.C.，S.T。和B.A.W.进行了实验并分析了数据。E、 M.L，L.S.，S.T.，B.A.W。和J.M.K.准备并编辑了手稿。S、 T.，B.A.W。和J.M.K.监督了这项工作。通讯作者通讯

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Reprints and permissionsAbout this articleCite this articleLynch, E.M., Hansen, H., Salay, L. et al. Structural basis for allosteric regulation of human phosphofructokinase-1.

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