施一公2014-04-14 5:24 PM

源自甲烷暖球菌属詹氏甲烷球菌的蛋白酶体的调节颗粒对基质的折叠和转运机制  Mechanism of substrate unfolding and translocation by the regulatory particle of the proteasome from Methanocaldococcus jannaschii.

论文摘要

在古细菌M.詹氏甲烷球菌(M.詹氏甲烷球菌)中,伴随着结合蛋白降解到核心颗粒(CP)的展开和易位,蛋白酶体调节颗粒(RP),即蛋白酶体激活核苷酸(PAN)的同源六聚体复形,能负责靶蛋白的识别。通过基于结构突变的指导,我们确定了对PAN功能至关重要的氨基酸和结构基序。关键残基排列了PAN的轴向通道,这形成了基板易位的明显途径。包括ATP酶结构域在内的PAN的II型子复形与CP结合后能驱动底物蛋白质依赖于ATP的展开,远端I型子复形在此能形成基板易位通道的入口。I型和II型子复形之间的连接体区段是PAN功能的基础,这意味着这些区域之间的功能性或机械性耦合。序列保守性表明了PAN功能的原则可能适用于真核生物的蛋白酶体RP中。 

Abstract
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.

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