U-box domain 2, a modified RING finger, found in nitric oxide synthase-interacting protein (NOSIP) and similar proteins
NOSIP, also known as endothelial NO synthase (eNOS)-interacting protein, p33RUL, is an E3 ubiquitin-protein ligase implicated in the control of airway and vascular diameter, mucosal secretion, NO synthesis in ciliated epithelium, and, therefore, of mucociliary and bronchial function. The loss of NOSIP may cause holoprosencephaly and facial anomalies including cleft lip/palate, cyclopia and facial midline clefting. NOSIP interacts with neuronal nitric oxide synthase (nNOS) and eNOS by inhibiting nitric oxide (NO) production. It acts as a novel type of modulator that promotes translocation of eNOS from the plasma membrane to intracellular sites, thereby uncoupling eNOS from plasma membrane caveolae and inhibiting NO synthesis. NOSIP also interacts with protein phosphatase PP2A and mediates the monoubiquitination of the PP2A catalytic subunit. Thus, it is a critical modulator of brain and craniofacial development in mice and a candidate gene for holoprosencephaly in humans. Moreover, NOSIP associates with the erythropoietin (Epo) receptor (EpoR), mediates ubiquitination of EpoR, and plays an essential role in erythropoietin-induced proliferation. NOSIP contains an atypical N-terminal RING-like U-box domain that is split into two parts by an interjacent stretch of 104 amino acid residues, as well as a C-terminal RING-like U-box domain. This model corresponds to the second U-box domain.
Jiyao W et al.(2023). "The conserved domain database in 2023.",