Prp19/Pso4 Is an Autoinhibited Ubiquitin Ligase Activated by Stepwise Assembly of Three Splicing Factors

被引：39

作者：

de Moura, Tales Rocha ^{[1
]}

Mozaffari-Jovin, Sina ^{[2
]}

Szabo, Csaba Zoltan Kibedi ^{[1
]}

Schmitzova, Jana ^{[1
]}

Dybkov, Olexandr ^{[2
]}

Cretu, Constantin ^{[1
]}

Kachala, Michael ^{[3
,4
]}

Svergun, Dmitri ^{[4
]}

Urlaub, Henning ^{[5
,6
]}

Luehrmann, Reinhard ^{[2
]}

Pena, Vladimir ^{[1
]}

机构：

[1] Max Planck Inst Biophys Chem, Macromol Crystallog Grp, Fassberg 11, D-37077 Gottingen, Germany

[2] Max Planck Inst Biophys Chem, Dept Cellular Biochem, Fassberg 11, D-37077 Gottingen, Germany

[3] Bayer, Dusseldorferstr 500,Geb 151, D-51061 Cologne, Germany

[4] European Mol Biol Lab, Biol Small Angle Scattering, Notkestr 85,Geb 25a, D-22607 Hamburg, Germany

[5] Max Planck Inst Biophys Chem, Bioanalyt Mass Spectrometry Grp, Fassberg 11, D-37077 Gottingen, Germany

[6] Univ Med Ctr Gottingen, Inst Clin Chem, Bioanalyt Grp, Robert Koch Str 40, D-37075 Gottingen, Germany

来源：

MOLECULAR CELL | 2018年 / 69卷 / 06期

关键词：

U-BOX PROTEINS; RING E3 LIGASE; DNA-DAMAGE; X-RAY; STRUCTURAL INSIGHTS; CRYOEM STRUCTURES; COMPLEX; SCATTERING; FAMILY; RPA;

D O I：

10.1016/j.molcel.2018.02.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Human nineteen complex (NTC) acts as a multimeric E3 ubiquitin ligase in DNA repair and splicing. The transfer of ubiquitin is mediated by Prp19-a homotetrameric component of NTC whose elongated coiled coils serve as an assembly axis for two other proteins called SPF27 and CDC5L. We find that Prp19 is inactive on its own and have elucidated the structural basis of its autoinhibition by crystallography and mutational analysis. Formation of the NTC core by stepwise assembly of SPF27, CDC5L, and PLRG1 onto the Prp19 tetramer enables ubiquitin ligation. Protein-protein crosslinking of NTC, functional assays in vitro, and assessment of its role in DNA damage response provide mechanistic insight into the organization of the NTC core and the communication between PLRG1 and Prp19 that enables E3 activity. This reveals a unique mode of regulation for a complex E3 ligase and advances understanding of its dynamics in various cellular pathways.

引用

页码：979 / +

页数：20

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