RING-CH finger, H2 subclass (C4HC3-type), found in membrane-associated RING-CH8 (MARCH8)
MARCH8, also known as membrane-associated RING finger protein 8, membrane-associated RING-CH protein VIII (MARCH-VIII), RING finger protein 178 (RNF178), or cellular modulator of immune recognition (c-MIR), is a membrane-anchored E3 ubiquitin ligase that is broadly expressed. It is a functional homolog of Kaposi"s sarcoma associated-herpes virus encoded proteins, modulator of immune recognition (MIR) 1 and 2, which are involved in the evasion of host immunity. MARCH8 mediates the ubiquitination and down-regulation of immune regulatory cell surface molecules, including major histocompatibility complex class II (MHCII), CD86, transferrin receptor, HLA-DM, and Fas in immune cells. Moreover, MARCH8 controls cell surface expression of some additional proteins. It regulates the ubiquitination and lysosomal degradation of the transferrin receptor (TfR). Tumor necrosis factor-related apoptosis inducing ligand receptor 1 (TRAIL-R1) is also a physiological substrate of the endogenous MARCH8, which regulates the steady-state cell surface expression of TRAIL-R1. Meanwhile, it negatively regulates interleukin-1 (IL-1) beta-induced NF-kappaB activation by targeting the IL-1 receptor accessory protein (IL1RAP) coreceptor for ubiquitination and degradation. Furthermore, MARCH8 functions in the embryo to modulate the strength of cell adhesion by regulating the localization of E-cadherin. In addition, MARCH8 plays a role in the inhibition of inflammatory cytokine production, suggesting a new therapeutic approach to the treatment of rheumatoid arthritis (RA). MARCH8 contains an N-terminal cytoplasmic C4HC3-type RING-CH finger, also known as vRING or RINGv, a variant of C3H2C3-type RING-H2 finger and two transmembrane domains.
Structure:2D8S; Homo sapiens MARCH8 binds two Zn2+ ions through its RING-CH finger. - View structure with Cn3D
Comment:RING-CH finger (C4HC3-type)
Comment:A RING finger typically binds two zinc atoms, with its Cys and/or His side chains in a unique "cross-brace" arrangement.
Comment:The RING fingers found in MARCH proteins have an unusual arrangement of zinc-coordinating residues: The conserved helix complete with tryptophan at the C-terminal end is present but the cysteines and histidines are arranged in the sequence as C4HC3-type, rather than the typical C3H2C3-type in RING-H2 finger.
Jiyao W et al.(2023). "The conserved domain database in 2023.",