| Primary Identifier | IPR060330 | Type | Domain |
| Short Name | RNF216_N |
| description | This entry represents a tri-helical domain found towards the N-terminal of E3 ubiquitin-protein ligase RNF216 (RING finger protein 216), also known as TRIAD3A. The specific function of this domain remains to be determined. The very N-terminal region contains multiple disordered regions and is subject to extensive sumoylation.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. |
