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  • AM251 The human MARCH family comprises eleven members

    2019-11-02

    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 phylogenetic 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 AM251 (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 RING-E3 ligases are often found both as monomers and homodimers, but heterodimers have also been reported [11]. However, the dimerisation interfaces can vary, and are grouped in two distinct types, the RINGv-mediated interfaces and the non-RINGv mediated interfaces [13]. E3 ligases have also been shown to exist as higher oligomers, as revealed by negative-stain electron microscopy for the tetrameric pre-mRNA splicing factor Prp19p [71]. Prp19p is a soluble U-box E3 ligase that is structurally related to RING-E3 ligases but lacks the eight canonical Zn2+-coordinating residues [72]. Oligomerisation for MARCH proteins was first shown for the viral MARCH kK5 by co-immunoprecipitation and the responsible region could be traced to the TM1-L1-TM2 fragment [73]. Next, MARCH-9 was shown to form oligomers with a truncated MARCH-9 protein lacking the RINGv domain by co-immunoprecipitation [69], also indicating that the RINGv-domain is not necessary for oligomerisation in MARCH proteins. Co-immunoprecipitation showed homo-oligomerisation for MARCH-1 and MARCH-8, as well as possible hetero-oligomerisation for MARCH-1/MARCH-8 and MARCH-1/MARCH-9 [74]. Furthermore, MARCH-1 homo-oligomerisation and MARCH-1/MARCH-8 hetero-oligomerisation was confirmed by bioluminescence resonance energy transfer (BRET) [74]. Importantly, these experiments do not exclude the formation of higher oligomers than dimers. Interestingly, co-immunoprecipitation studies with MARCH-1 chimeras, which either had TM1, TM2 or both TM helices replaced by MARCH-9 TM helices, revealed that oligomerisation with MARCH-1 was only rescued when both TM1 and TM2 were exchanged [75]. In conclusion, the oligomerisation of MARCH proteins is most likely only mediated by the TM helices with little or no contribution from the RINGv-domains.
    Ubiquitination of MARCH target proteins The RING-E3 ligase activity requires MARCH proteins to simultaneously bind a cognate E2 conjugating enzyme and a substrate protein. Ubiquitination of MARCH target proteins takes place on the cytosolic side [22], [36], [76] inline with binding of E2 proteins to the cytosolic RINGv domain.