| Description | This entry represents the BRcat domain of RNF216 and similar proteins from animals and fungi. This domain adopts the same fold as the Rcat domain while lacking the catalytic cysteine residue and ubiquitination activity.E3 ubiquitin-protein ligase RNF216, also known as Triad domain-containing protein 3 (Triad3A), is a RBR-type E3 ubiquitin-protein ligase that interacts with several components of Toll-like receptor (TLR) signalling and promotes their proteolytic degradation. It negatively regulates the RIG-I RNA sensing pathway through Lys48-linked, ubiquitin-mediated degradation of the tumour necrosis factor receptor-associated factor 3 (TRAF3) adapter following RNA virus infection. It also controls ubiquitination and proteasomal degradation of receptor-interacting protein 1 (RIP1), a serine/threonine protein kinase that is critically involved in tumour necrosis factor receptor-1 (TNF-R1)-induced NF-kappa B activation, following disruption of Hsp90 binding. Moreover, RNF216 is involved in inflammatory diseases through strongly inhibiting autophagy in macrophages. It interacts with and ubiquitinates BECN1, a key regulator in autophagy, thereby contributing to BECN1 degradation. It regulates synaptic strength by ubiquitination of Arc, resulting in its rapid proteasomal degradation. It is also a key negative regulator of sustained Killer cell Ig-like receptor (KIR) with two Ig-like domains and a long cytoplasmic domain 4 (2DL4)-mediated NF-kappaB signalling from internalized 2DL4, which functions by promoting ubiquitylation and degradation of endocytosed receptor from early endosomes [ , , , , , , ]. Furthermore, RNF216 interacts with HIV-1 Virion infectivity factor (Vif) protein, which is essential for the productive infection of primary human CD4 T lymphocytes and macrophages []. Mutations in RNF216 may result in Gordon Holmes syndrome, a condition defined by hypogonadotropic hypogonadism and cerebellar ataxia, as well as in autosomal recessive Huntington-like disorder [, ].RNF216 contains a RBR domain that was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been corrected as RING-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR (RING1-BRcat-Rcat) domain use an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase function to facilitate the ubiquitination reaction. | Name | E3 ubiquitin-protein ligase RNF216, BRcat domain |
| Short Name | BRcat_RBR_RNF216 | Type | Domain |
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