UEV Domains

UEV (ubiquitin E2 variant) domains are homologs of ubiquitin E2 ligases that lack the active-site cysteine, but retain the capability of ubiquitin binding, which is often of functional importance. Human UEV1a as well as its yeast homolog Mms2, for example, are involved in polyubiquitin chain assembly (Hofmann and Pickart 1999; Deng et al. 2000; VanDemark et al. 2001). Interaction with proline-rich motifs, however, has only been described for the UEV domain of human Tsg101 (tumor-susceptibility gene 101) and its yeast homolog Vps23. PRM recognition of Tsg101-UEV plays a pivotal role in endosomal sorting (Williams and Urbe 2007; Hurley and Emr 2006; Babst 2005) and has recently been shown to be essential for the budding of HIV and other enveloped viruses (Pornillos et al. 2002b; Morita and Sundquist 2004; Bieniasz 2006). The P(T/S)AP motif of HIV-1 is called the L (late) domain, because it is essential for the late budding step of pinching off the plasma membrane (Gottlinger et al. 1991; Huang et al. 1995). This L-domain was shown to interact with Tsg101-UEV (Garrus et al. 2001; VerPlank et al. 2001), presumably recruiting the ESCRT machinery to the budding site at the plasma membrane. Thereby, viruses might mimic the function of the cellular protein Hrs that is assumed to recruit the ESCRT machinery to the endosomal membrane via a PSAP-UEV interaction (Pornillos et al. 2003). As Tsg101-UEV is essential for HIV replication, the Tsg-UEV/HIV-PTAP interaction is an attractive target for the development of antiviral compounds. These compounds should very specifically target the PRM recognition site within the UEV domain as is guaranteed by a proline-mimetic approach described by Liu and colleagues (2006). Such a strategy might make it possible to inhibit virus replication without interfering with other functions of Tsg101 such as cell proliferation and survival (Krempler et al. 2002; Wagner et al. 2003; Carstens et al. 2004). This is supported by the finding that overexpression of the N-terminal (UEV) domain of Tsg101 efficiently blocks HIV release, while overexpression of the C-terminal domain or full-length Tsg101 results in aberrant endsosomes (Demirov et al. 2002; Goila-Gaur et al. 2003).

0 0

Post a comment