Abstract

The LYPxL motif recruits the cellular protein Alix (ALG2-interacting protein-1, or AIP1), which is associated with the Endosomal Sorting Complex Required for Transport (ESCRT). The ESCRT system is involved in the selective trafficking of membrane proteins to the lysosome by incorporating the membrane proteins into multivesicular bodies (MVBs). The final step in the biogenesis of MVBs is the ESCRT-mediated abscission of the cargo-containing vesicular membrane from the perimeter membrane (reviewed in 19325624). Some viruses have evolved strategies to hijack this process, which enables them to use ESCRT for the budding of viral particles from the host cell membrane.



Short peptide sequences within viral Gag proteins (encoding the structural proteins of the virus) are required for the separation of the virus from the host cell membrane. These sequences are called late assembly (L-)domains and mediate the interaction with components of ESCRT. So far, three different L-domains have been extensively studied: PTAP, PPxY and LYPxL. These L-domains can function individually as well as cooperatively, and were demonstrated to be interchangeable between different viruses (reviewed in 15567490).



The LYPxL motif was first characterized as a functional L-domain in EIAV by Puffer et al. (9811764). Gottlinger et al. established the link between the LYPxL motif and ESCRT by identifying the ESCRT associated protein Alix as a binding partner of LYPxL (14505569). The recruitment of Alix is used to direct further members of ESCRT to the viral budding site, assembling the budding complex, which mediates the release of viral particles from the host cell. In this way, Alix acts as a bridging factor between ESCRT I and ESCRT III by binding both Tsg101 (ESCRT I) and CHMP4 (ESCRT III) (19865606).



The importance of the LYPxL motif in viral budding varies among different viruses, depending on the presence of other L-domains. LYPxL is essential for budding if it is the only L-domain motif present, as in EIAV. In contrast, other viruses such as HIV-1 possess more complex L-domains that can include two other ESCRT related motifs PTAP and PPxY that also contribute to efficient viral budding (16364736). In general, the role of the LYPxL L-domain in viral budding is considered to be minor compared to PPxY and PTAP (20392845).



The LYPxL motif binds to a hydrophobic pocket located in the central V-domain of Alix. The binding is stabilized mostly by van-der-Waals interactions as well as a few hydrogen bonds. Within the LYPxL motif, two flanking hydrophobic residues as well as tyrosine are considered to be crucial for the binding (18066081). The number of random residues tolerated at the fourth position is restricted to either one or three amino acids.



As this entry was prepared, there was only one cellular (non-viral) instance of the LYPxL motif reported: the pH-response transcription factor PacC in Aspergillus nidulans. PacC undergoes a two-step proteolytic activation as a response to alkaline pH. The Alix homolog PalA is required to direct a signalling protease to the cleavage sites of PacC. PacC contains two LYPxL motifs, one at each cleavage site to recruit PalA (12588984). Until more cellular LYPxL motifs are identified, it will be difficult to assess the role of the motif in vesicular trafficking of the cell.



Two variant motifs - short and long - have so far been identified in various viruses and each is given a separate regular expression in ELM.