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. The short version of the LYPxL motif contains one random amino acid at the fourth position. This spacing amino acid points away from the Alix surface and is therefore not involved in any specific interactions, explaining the low conservation of this position. The fifth position of the motif is most commonly adopted by either leucine or isoleucine. The affinity of LYPDL in EIAV to Alix is 1.5 micromolar (Zhai,2008). The derived pattern for the short version of the LYPxL motif is [LM]YPx[LI].
Pattern: [LM]YP.[LI]
Pattern Probability: 0.0000123
Present in taxon: Eukaryota
Interaction Domain:
ALIX_LYPXL_bnd (PF13949) ALIX V-shaped domain binding to HIV (Stochiometry: 1 : 1)
PDB Structure: 2R03
o See 16 Instances for LIG_LYPXL_S_1
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 11 selected references:

o 9 GO-Terms:

o 16 Instances for LIG_LYPXL_S_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
O00560 SDCBP
49 53 DGNLYPRLYPELSQYMGLSL TP 0 Homo sapiens (Human)
O00560 SDCBP
45 49 PIPHDGNLYPRLYPELSQYM TP 0 Homo sapiens (Human)
O00560 SDCBP
3 7 MSLYPSLEDLKVDKVIQAQT TP 0 Homo sapiens (Human)
P03322 gag-pro
180 184 PPYVGSGLYPSLAGVGEQQG TP 1 Rous sarcoma virus - Prague C
Q00202 pacC
661 665 ESAEDSVMYPTLRGLDEDGD TP 1 Aspergillus nidulans
Q00202 pacC
454 458 PHESGSSMYPRLPSATDGMT TP 1 Aspergillus nidulans
Q83383 gag
128 132 QPPPRSALYPALTPSIKPRP TP 1 Murine leukemia virus
P69732 gag
457 461 ETPQTQNLYPDLSEIKKEYN TP 6 Equine infectious anemia virus (ISOLATE WYOMING)
P03355 gag-pol
130 134 STPPRSSLYPALTPSLGAKP TP 3 Moloney murine leukemia virus
Q27ID9 gag
128 132 QPPSRSALYPALTPSIKSKP TP 1 Xenotropic MuLV-related virus VP62
P03331 gag
128 132 QPPPRSALYPALTPSIKPGP TP 1 Friend spleen focus-forming virus (isolate 502)
P03334 gag
130 134 STPPQSSLYPALTPSLGAKP TP 1 Moloney murine sarcoma virus
P21435 gag
128 132 GPPTRSSLYPALTPTKSPSP TP 1 HoMuLV murine leukemia virus
P26806 gag
130 134 STPPQSSLYPALTSPLNTKP TP 1 Friend murine leukemia virus (ISOLATE FB29)
P03340 gag
P29175 gag
128 132 QPPPRSALYPALTPSIKPRP TP 1 FBR murine osteosarcoma virus
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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