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  • br MARCH E ligases A specific family of eukaryotic E

    2020-07-31


    MARCH E3 ligases A specific family of eukaryotic E3 ligases that has received additional attention recently consists of the embrane-ssociated ING- (MARCH) proteins. Initially, two viral MARCH-homologue gene products were discovered in Kaposi\'s sarcoma (KS)-associated herpesvirus (KSHV), and subsequently named K3 (kK3) and K5 (kK5). Later, kK3- and kK5-related E3s were found in poxviruses and a K3-related E3 ligase was discovered in myxomavirus (termed mK3) [18]. These viral MARCH E3s help escape from host defence mechanisms by down-regulating major histocompatibility complex (MHC) class I (MHC‐I) antigen presentation and are now thought to originate from the human MARCH proteins due to their overlapping substrate spectrum and structural similarity [18], [19], [20]. Interestingly, viral MARCHs are often able to ubiquinate their targets on non-lysine residues, such as cysteine, serine and threonine residues [19], [21], [22]. The human MARCH family comprises eleven members (termed MARCH-1 to 11), of which nine are transmembrane proteins. In this review, we focus on the role of the membrane-spanning MARCH proteins and how their transmembrane regions can mediate interactions with their target proteins. Therefore, the cytosolic MARCH-7 and MARCH-10 proteins are not regarded here (but have been reviewed elsewhere [19], [23]). MARCH proteins show overlapping substrate specificity (Table 1), and this can be rationalised by factor xa inhibitor analysis (Fig. 1). Even though some MARCHs ubiquitinate the same substrate, they might do so in different cellular compartments, at different time points, and with a different ubiquitination pattern resulting in differential sorting of their target proteins into different cellular pathways[24], [25], [26].
    Architecture of human MARCH proteins Human MARCH proteins share the RINGv domain (∼6kDa) that coordinates two Zn2+ ions in a cross-braced manner for recognition of a cognate E2 protein. MARCH-7 and MARCH-10 are soluble non-membrane associated E3 ligases with the RINGv domain at the C-terminus, whereas the other family members are membrane-embedded proteins with two transmembrane (TM) helices predicted in MARCH-1/8, MARCH-2/3, and MARCH-4/9/11, four in MARCH-5 and 14 in MARCH-6 (Fig. 1). The RINGv domain is always placed N-terminal to the first TM helix at a distance of approximately 13–36 residues from the first TM helix. TM1 and TM2 are themselves connected via a 13–27 amino acid (aa) long luminal loop (L1). This RINGv-TM1/2 segment is often confined either by disordered stretches (i) before the RINGv domain (MARCH-1/8), (ii) after the TM2 helix (MARCH-6), (iii) on both sides (MARCH-4/9/11), or (iv) by sequence boundaries, i.e. that the RINGv is already placed at the very N-terminus of the sequence (MARCH-5 and MARCH-6). Thus, the common structural element in membrane-embedded MARCH proteins is a cytosolic RINGv domain followed by two transmembrane helices (Fig. 1).
    Oligomerisation of MARCH proteins