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Structural insights into ubiquitin recognition and Ufd1 interaction of Npl4.

Nat Commun. 2019 Dec 13;10(1):5708
Yusuke Sato 1 , Hikaru Tsuchiya 2 , Atsushi Yamagata 3 , Kei Okatsu 4 , Keiji Tanaka 2 , Yasushi Saeki 5 , Shuya Fukai 6
Yusuke Sato 1 , Hikaru Tsuchiya 2 , Atsushi Yamagata 3 , Kei Okatsu 4 , Keiji Tanaka 2 , Yasushi Saeki 5 , Shuya Fukai 6
+ et al

[No authors listed]

Author information
  • 1 Center for Research on Green Sustainable Chemistry, Tottori University, Tottori, 680-8582, Japan.
  • 2 Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.
  • 3 RIKEN Center for Biosystems Dynamics Research, Kanagawa, 230-0045, Japan.
  • 4 Synchrotron Radiation Research Organization, The University of Tokyo, Tokyo, 113-0032, Japan.
  • 5 Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan. saeki-ys@igakuken.or.jp.
  • 6 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, 277-8562, Japan. fukai@iam.u-tokyo.ac.jp.

摘要


Npl4 is likely to be the most upstream factor recognizing Lys48-linked polyubiquitylated substrates in the proteasomal degradation pathway in yeast. Along with Ufd1, Npl4 forms a heterodimer (UN), and functions as a cofactor for the Cdc48 ATPase. Here, we report the crystal structures of yeast Npl4 in complex with Lys48-linked diubiquitin and with the Npl4-binding motif of Ufd1. The distal and proximal ubiquitin moieties of Lys48-linked diubiquitin primarily interact with the C-terminal helix and N-terminal loop of the Npl4 C-terminal domain (CTD), respectively. Mutational analysis suggests that the CTD contributes to linkage selectivity and initial binding of ubiquitin chains. Ufd1 occupies a hydrophobic groove of the Mpr1/Pad1 N-terminal (MPN) domain of Npl4, which corresponds to the catalytic groove of the MPN domain of JAB1/MPN/Mov34 metalloenzyme (JAMM)-family deubiquitylating enzyme. This study provides important structural insights into the polyubiquitin chain recognition by the Cdc48-UN complex and its assembly.