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Structure paper

タイトル	The structure of the PA28-20S proteasome complex from Plasmodium falciparum and implications for proteostasis.
ジャーナル・号・ページ	Nat Microbiol, Vol. 4, Issue 11, Page 1990-2000, Year 2019
掲載日	2019年8月5日
著者	Stanley C Xie / Riley D Metcalfe / Eric Hanssen / Tuo Yang / David L Gillett / Andrew P Leis / Craig J Morton / Michael J Kuiper / Michael W Parker / Natalie J Spillman / Wilson Wong / Christopher Tsu / Lawrence R Dick / Michael D W Griffin / Leann Tilley /
PubMed 要旨	The activity of the proteasome 20S catalytic core is regulated by protein complexes that bind to one or both ends. The PA28 regulator stimulates 20S proteasome peptidase activity in vitro, but its ...The activity of the proteasome 20S catalytic core is regulated by protein complexes that bind to one or both ends. The PA28 regulator stimulates 20S proteasome peptidase activity in vitro, but its role in vivo remains unclear. Here, we show that genetic deletion of the PA28 regulator from Plasmodium falciparum (Pf) renders malaria parasites more sensitive to the antimalarial drug dihydroartemisinin, indicating that PA28 may play a role in protection against proteotoxic stress. The crystal structure of PfPA28 reveals a bell-shaped molecule with an inner pore that has a strong segregation of charges. Small-angle X-ray scattering shows that disordered loops, which are not resolved in the crystal structure, extend from the PfPA28 heptamer and surround the pore. Using single particle cryo-electron microscopy, we solved the structure of Pf20S in complex with one and two regulatory PfPA28 caps at resolutions of 3.9 and 3.8 Å, respectively. PfPA28 binds Pf20S asymmetrically, strongly engaging subunits on only one side of the core. PfPA28 undergoes rigid body motions relative to Pf20S. Molecular dynamics simulations support conformational flexibility and a leaky interface. We propose lateral transfer of short peptides through the dynamic interface as a mechanism facilitating the release of proteasome degradation products.
リンク	Nat Microbiol / PubMed:31384003
手法	EM (単粒子) / X線回折
解像度	3.1 - 4.6 Å
構造データ	EMDB-20073: Reconstruction of the Plasmodium falciparum 20S proteasome in complex with one PA28 activator prepared without chemical stabilisation 手法: EM (単粒子) / 解像度: 4.6 Å 9257 6muv EMDB-9257: The structure of the Plasmodium falciparum 20S proteasome in complex with two PA28 activators. PDB-6muv: The structure of the Plasmodium falciparum 20S proteasome in complex with two PA28 activators 手法: EM (単粒子) / 解像度: 3.8 Å 9258 6muw EMDB-9258, PDB-6muw: The structure of the Plasmodium falciparum 20S proteasome. 手法: EM (単粒子) / 解像度: 3.6 Å 9259 6mux EMDB-9259: The structure of the Plasmodium falciparum 20S proteasome in complex with one PA28 activator. PDB-6mux: The structure of the Plasmodium falciparum 20S proteasome in complex with one PA28 activator 手法: EM (単粒子) / 解像度: 3.9 Å PDB-6dfk: Crystal structure of the 11S subunit of the Plasmodium falciparum proteasome, PA28 手法: X-RAY DIFFRACTION / 解像度: 3.1 Å
化合物	ChemComp-SO4: SULFATE ION / 硫酸ジアニオン / 硫酸塩
由来	plasmodium falciparum 3d7 (マラリア病原虫) plasmodium falciparum (isolate 3d7) (マラリア病原虫) plasmodium falciparum (マラリア病原虫)
キーワード	PROTEIN BINDING (タンパク質) / 11S proteasome subunit / 11S regulatory particle / PA28 / REG / proteasome activator / hydrolase activator / HYDROLASE (加水分解酵素) / proteasome (プロテアソーム) / protease (プロテアーゼ) / 11S subunit / hydrolyse activator / complex