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Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP

DOI: 10.1038/nature12638 DOI Help
PMID: 24141947 PMID Help

Authors: Ben Stieglitz (MRC National Institute for Medical Research) , Rohini Rana (MRC National Institute for Medical Research) , Marios Koliopoulos (MRC National Institute for Medical Research) , Aylin C. Morris-Davies (MRC National Institute for Medical Research) , Veronique Schaeffer (Goethe University) , Evangelos Christodoulou (MRC National Institute for Medical Research) , Steven Howell (MRC National Institute for Medical Research) , Nick Brown (MRC National Institute for Medical Research) , Ivan Dikic (Goethe University) , Katrin Rittinger (MRC National Institute for Medical Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature

State: Published (Approved)
Published: October 2013
Diamond Proposal Number(s): 7707

Abstract: Linear ubiquitin chains are important regulators of cellular signalling pathways that control innate immunity and inflammation through nuclear factor (NF)-κB activation and protection against tumour necrosis factor-α-induced apoptosis1,2,3,4,5. They are synthesized by HOIP, which belongs to the RBR (RING-between-RING) family of E3 ligases and is the catalytic component of LUBAC (linear ubiquitin chain assembly complex), a multisubunit E3 ligase6. RBR family members act as RING/HECT hybrids, employing RING1 to recognize ubiquitin-loaded E2 while a conserved cysteine in RING2 subsequently forms a thioester intermediate with the transferred or ‘donor’ ubiquitin7. Here we report the crystal structure of the catalytic core of HOIP in its apo form and in complex with ubiquitin. The carboxy-terminal portion of HOIP adopts a novel fold that, together with a zinc-finger, forms a ubiquitin-binding platform that orients the acceptor ubiquitin and positions its α-amino group for nucleophilic attack on the E3∼ubiquitin thioester. The C-terminal tail of a second ubiquitin molecule is located in close proximity to the catalytic cysteine, providing a unique snapshot of the ubiquitin transfer complex containing both donor and acceptor ubiquitin. These interactions are required for activation of the NF-κB pathway in vivo, and they explain the determinants of linear ubiquitin chain specificity by LUBAC.

Journal Keywords: Catalytic; Crystallography; X-Ray; HeLa; Humans; Models; Molecular; Protein; Substrate; Ubiquitin; Ubiquitin-Protein Ligases

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 23/10/2013 11:33

Discipline Tags:

Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)