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Structural basis for ubiquitylation by HOIL-1.

Qilong Wu1, Marios G Koliopoulos2, Katrin Rittinger2

  • 1Department of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of London, London, United Kingdom.

Frontiers in Molecular Biosciences
|January 23, 2023
PubMed
Summary
This summary is machine-generated.

The linear ubiquitin chain assembly complex (LUBAC) component HOIL-1 uses linear tetra-ubiquitin binding to mono-ubiquitylate targets. Its unique RING2 domain structure with a bi-nuclear zinc cluster is key to this activity.

Keywords:
E3 ligaseHOIL-1LHOIPLUBACRBCK1TNF signallingamylopectinosisubiquitin

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Signaling

Background:

  • The linear ubiquitin chain assembly complex (LUBAC) is crucial for TNF signaling.
  • HOIL-1, a LUBAC component, exhibits ligase activity, forming oxyester linkages.
  • Understanding HOIL-1's mechanism is vital for comprehending LUBAC function.

Purpose of the Study:

  • To elucidate the mechanism of HOIL-1 ubiquitylation activity.
  • To determine the structural basis for HOIL-1's substrate recognition and catalysis.
  • To investigate the role of linear ubiquitin chain binding in HOIL-1 function.

Main Methods:

  • Biochemical assays to study HOIL-1 activity.
  • Crystal structure determination of HOIL-1's C-terminal tandem domain (IBR and RING2).
  • Site-directed mutagenesis to identify key catalytic residues.

Main Results:

  • HOIL-1 activity is dependent on binding linear tetra-ubiquitin chains.
  • The crystal structure of HOIL-1's IBR-RING2 domains reveals a unique bi-nuclear zinc cluster in the RING2 domain.
  • A C-terminal histidine within the bi-nuclear zinc cluster is identified as the catalytic base for ubiquitylation.

Conclusions:

  • HOIL-1's unique RING2 zinc-coordinating architecture facilitates substrate binding.
  • Linear ubiquitin chain binding is essential for HOIL-1's mono-ubiquitylation activity.
  • This study provides structural and mechanistic insights into LUBAC-mediated signaling.