施一公2佳作齐登同期《细胞》子刊

　　

生物通报道，近期清华大学生物科学与技术学院结构生物学中心施一公在Cell子刊《Molecular Cell》同期发表两篇文章，文章一Mechanism of Substrate Unfolding and Translocation by the Regulatory Particle of the Proteasome from Methanocaldococcus jannaschii及文章二Structural Insights into the Regulatory Particle of the Proteasome from Methanocaldococcus jannaschii。

 

两篇文章的通讯作者都是施一公教授，其余作者分别来自哈佛大学医学院细胞生物学系和普林斯顿大学分子生物学系Lewis Thomas实验室。

 

两篇文章均以Methanocaldococcus jannaschii为研究对象，研究蛋白酶体（proteasome）的结构与活性。真核生物的蛋白酶体都可分为两个区域，一个核心区域（core particle，CP）和调节区域（regulatory particle，RP）。CP具有催化活性，其降解产物是非折叠结构的蛋白，RP负责识别酶底物，识别依赖ATP的非折叠区域，促进酶异构产生酶活性。

 

在Structural Insights into the Regulatory Particle of the Proteasome from Methanocaldococcus jannaschii文章，施一公研究小组主要分析了调节区域（RP）的三维晶体结构。

 

在Mechanism of Substrate Unfolding and Translocation by the Regulatory Particle of the Proteasome from Methanocaldococcus jannaschii文章，施一公研究小组主要分析了调节区域RP的酶底物结合位点与异构位点的结构机制。

 

这些研究成果对研究蛋白酶体的保守性，以及蛋白酶体的功能活性结构具有重要的指导意义。

（生物通 小茜）

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文章一

Structural Insights into the Regulatory Particle of the Proteasome from Methanocaldococcus jannaschii

 

Fan Zhang1,Min Hu1,Geng Tian2,Ping Zhang1,Daniel Finley2,Philip D. Jeffrey1andYigong Shi3,,

1 Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA

2 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA

3 Center for Structural Biology, Department of Biological Sciences and Biotechnology and the School of Medicine, Tsinghua University, Beijing 100084, China

Corresponding author

【Summary】

Eukaryotic proteasome consists of a core particle (CP), which degrades unfolded protein, and a regulatory particle (RP), which is responsible for recognition,ATP-dependent unfolding, and translocation of polyubiquitinated substrate protein. In the archaea Methanocaldococcus jannaschii, the RP is a homohexameric complex of proteasome-activating nucleotidase (PAN). Here, we report the crystal structures of essential elements of the archaeal proteasome:the CP, the ATPase domain of PAN, and a distal subcomplex that is likely the first to encounter substrate. The distal subcomplex contains a coiled-coil segment andan OB-fold domain, both of which appear to be conserved in the eukaryotic proteasome. The OB domains of PAN form a hexameric ring with a 13 Å pore, which likely constitutes the outermost constriction of the substrate translocation channel. These studies reveal structural codes and architecture ofthe complete proteasome, identify potential substrate-binding sites, and uncover unexpected asymmetry in the RP of archaea and eukaryotes.

 

文章二

Mechanism of Substrate Unfolding and Translocation by the Regulatory Particle of the Proteasome from Methanocaldococcus jannaschii

 

Fan Zhang1,Zhuoru Wu1,Ping Zhang1,Geng Tian2,Daniel Finley2andYigong Shi3,,

1 Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA

2 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA

3 Center for Structural Biology, Department of Biological Sciences and Biotechnology and the School of Medicine, Tsinghua University, Beijing 100084, China

Corresponding author

【Summary】

In the archaebacterium Methanocaldococcus jannaschii (M. jannaschii), the proteasomal regulatory particle (RP), a homohexameric complex of proteasome-activating nucleotidase (PAN), is responsible for target protein recognition, followed by unfolding and translocation of the bound protein into the core particle (CP) for degradation. Guided by structure-based mutagenesis, we identify amino acids and structural motifs that are essential for PAN function. Key residues line the axial channel of PAN, defining the apparent pathway of substrate translocation. Subcomplex II of PAN, comprising the ATPase domain, associates with the CP and drives ATP-dependent unfolding of the substrate protein, whereas the distal subcomplex I forms the entry port of the substrate translocation channel. A linker segment between subcomplexes I and II is essential for PAN function, implying functional and perhaps mechanical coupling between these domains. Sequence conservation suggests that the principles of PAN function are likely to apply to the proteasomal RP of eukaryotes.