5B83

Crystal structure of Optineurin UBAN in complex with linear ubiquitin

Summary for 5B83

• Entry DOI: 10.2210/pdb5b83/pdb
• Descriptor: tetra ubiquitin, Optineurin (3 entities in total)
• Functional Keywords: ubiquitin, coiled-coil, cellular, signaling, nfkb pathway, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 114971.48

Authors

Ishii, R.,Nureki, O. (deposition date: 2016-06-12, release date: 2016-09-07, Last modification date: 2023-11-08)

Primary citation

Nakazawa, S.,Oikawa, D.,Ishii, R.,Ayaki, T.,Takahashi, H.,Takeda, H.,Ishitani, R.,Kamei, K.,Takeyoshi, I.,Kawakami, H.,Iwai, K.,Hatada, I.,Sawasaki, T.,Ito, H.,Nureki, O.,Tokunaga, F.
Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis
Nat Commun, 7:12547-12547, 2016

PubMed Abstract: Optineurin (OPTN) mutations cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and glaucoma. Although the ALS-associated E478G mutation in the UBAN domain of OPTN reportedly abolishes its NF-κB suppressive activity, the precise molecular basis in ALS pathogenesis still remains unclear. Here we report that the OPTN-UBAN domain is crucial for NF-κB suppression. Our crystal structure analysis reveals that OPTN-UBAN binds linear ubiquitin with homology to NEMO. TNF-α-mediated NF-κB activation is enhanced in OPTN-knockout cells, through increased ubiquitination and association of TNF receptor (TNFR) complex I components. Furthermore, OPTN binds caspase 8, and OPTN deficiency accelerates TNF-α-induced apoptosis by enhancing complex II formation. Immunohistochemical analyses of motor neurons from OPTN-associated ALS patients reveal that linear ubiquitin and activated NF-κB are partially co-localized with cytoplasmic inclusions, and that activation of caspases is elevated. Taken together, OPTN regulates both NF-κB activation and apoptosis via linear ubiquitin binding, and the loss of this ability may lead to ALS.

PubMed: 27552911
DOI: 10.1038/ncomms12547

Experimental method

X-RAY DIFFRACTION (2.694 Å)