The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
LYPxL motif
Functional site description:
The LYPxL motif binds to the V-domain of eukaryotic Alix. Alix is associated with the ESCRT system, which is involved in endosomal sorting of membrane proteins. Most functional instances of the motif are known from retroviruses that use the host ESCRT system to bud from the cellular plasma membrane. In viruses, the LYPxL motif comprises a viral late assembly domain (L-domain). L-domains, located in viral Gag proteins, are required for the release of virions from the host cell.
ELMs with same func. site: LIG_LYPXL_L_2  LIG_LYPXL_S_1 
ELM Description:
The LYPxL motif binds to a hydrophobic groove in the central V-domain of Alix (Lee,2007). The binding is stabilized by both hydrophobic interactions as well as by a few important hydrogen bonds. The 3D structure of LYPxL in complex with Alix has been solved using X-ray crystallography (Zhai,2008). The two hydrophobic residues flanking the LYPxL motif make important hydrophobic contacts with Alix. Their substitution with alanine abrogates the binding. At the first position mostly leucine and rarely methionine occur. The second position of the motif is highly conserved, tolerating solely tyrosine. It inserts deep into the hydrophobic groove of Alix forming a hydrogen bond with a key conserved aspartate in the base of the groove. Mutational analyses have shown that substitution of tyrosine to phenylalanine impedes binding. Proline at position three is also highly conserved. It leans against three hydrophobic residues on the Alix surface. At the fourth position of the LYPxL motif, one or three random amino acids are tolerated. These spacing amino acids point away from the Alix surface and are therefore not involved in any specific interactions, explaining the low conservation of these positions. The long version of the LYPxL motif contains three spacing amino acids that adopt a helical conformation in order to fit three amino acids into the limited space available at the interaction site (Sharma,2010). Furthermore an additional hydrophobic residue (mostly leucine), seems to be needed three positions downstream of the actual motif to contribute to a stable helical structure. Thereby the LYPxL pattern is extended to LYPxxxLxxL. The affinity of LYPLTSLRSL in HIV-1 to Alix is 40 micromolar (Zhai,2008). The derived pattern for the long version of the LYPxL motif is [LM]xxx[LI]xx[LI].
Pattern: [LM]YP...[LI][^P][^P][LI]
Pattern Probability: 0.0000010
Present in taxon: Eukaryota
Interaction Domain:
ALIX_LYPXL_bnd (PF13949) ALIX V-shaped domain binding to HIV (Stochiometry: 1 : 1)
PDB Structure: 2R02
o See 3 Instances for LIG_LYPXL_L_2
o 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 Raiborg,2009). 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 Demirov,2004).
The LYPxL motif was first characterized as a functional L-domain in EIAV by Puffer,1998. Gottlinger,1991 established the link between the LYPxL motif and ESCRT by identifying the ESCRT associated protein Alix as a binding partner of LYPxL (Strack,2003). 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) (Pincetic,2009).
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 (Bieniasz,2006). In general, the role of the LYPxL L-domain in viral budding is considered to be minor compared to PPxY and PTAP (Dilley,2010).
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 (Zhai,2008). 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 (Vincent,2003). 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 (LIG_LYPXL_S_1) and long (LIG_LYPXL_L_2) - have so far been identified in various viruses and each is given a separate regular expression in ELM.
o 10 selected references:

o 9 GO-Terms:

o 3 Instances for LIG_LYPXL_L_2
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P04591 gag
P03347 gag
495 504 PIDKELYPLTSLRSLFGNDP TP 7 Human immunodeficiency virus type 1 BH10
P17282 gag
491 500 EGESSLYPPTSLKSLFGSDP TP 2 Simian immunodeficiency virus
Please cite: The eukaryotic linear motif resource - 2018 update. (PMID:29136216)

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