The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
Atg8 protein family ligands
Functional site description:
The autophagy-related protein Atg8 and its homologues LC3 and GABARAP play an important role in selective autophagy. During autophagy, Atg8 proteins get directly conjugated to phosphatidylethanolamine (PE) lipids to mediate membrane fusion events involved in autophagosome biogenesis such as phagophore formation and elongation. In addition, different Atg8 protein family members can recruit specific adaptors bound to ubiquitylated proteins, organelles or pathogens for degradation. Many of these adaptor proteins contain an LC3-interacting region (LIR) that mediates binding to Atg8 and Atg8-related proteins. These LIR:Atg8/LC3/GABARAP interactions are essential for cellular cell homeostasis as well as the control of intra- and extracellular stress conditions.
ELMs with same tags:
ELMs with same func. site: LIG_LIR_Apic_2  LIG_LIR_Gen_1  LIG_LIR_LC3C_4  LIG_LIR_Nem_3 
ELM Description:
The core of the LIR motif is defined by four amino acids and adopts a beta-strand conformation that forms an intermolecular parallel beta-sheet with the second beta-strand of Atg8 protein family members (Rogov,2014). There is an absolute requirement for an aromatic residue at the N-terminal side of the core motif and a large, hydrophobic residue at the C-terminal side. Structural studies have revealed that the side chain of the aromatic residue of the LIR motif binds deeply in HP1 whereas the hydrophobic residue docks to HP2 (2ZJD) (Ichimura,2008). The two amino acids in between these conserved positions are variable. The core motif is generally preceded by a varying number of acidic residues or by serine or threonine residues that can be phosphorylated to incorporate a negative charge. These residues commonly occur within three positions N-terminal to the core motif. The negative charge of these acidic or phosphorylated residues has been shown to strengthen the LIR:Atg8/LC3/GABARAP interaction (Rogov,2013). Additional acidic residues or serine/threonine phosphorylation sites that strengthen the interaction are sometimes observed in the undefined positions between the aromatic and hydrophobic residue. The side chain of the aromatic residue binds deeply in HP1. A tryptophan residue is energetically favored for this interaction over a tyrosine or phenylalanine residue, but the lower binding affinity can be compensated by electrostatic interactions between acidic residues or serine/threonine phosphorylation sites of the LIR motif and basic residues in the N-terminal arm of the Atg8 homologues (Wild,2013).
Pattern: [EDST].{0,2}[WFY][^RKPG][^PG][ILV]
Pattern Probability: 0.0030570
Present in taxon: Eukaryota
Not represented in taxons: Apicomplexa Nematoda
Interaction Domain:
Atg8 (PF02991) Autophagy protein Atg8 ubiquitin like (Stochiometry: 1 : 1)
PDB Structure: 2L8J
o See 21 Instances for LIG_LIR_Gen_1
o Abstract
Macroautophagy is an evolutionary conserved degradation process that targets macromolecules and organelles and is of vital importance for cellular homeostasis. In this process, a double membrane structure called the phagophore forms and expands to form a double-membrane vesicle, the autophagosome. Autophagosomes then sequester cargo and eventually fuse with the vacuole in yeast or the lysosome in higher eukaryotes in order to degrade their content (Mizushima,2011). Several autophagy-related proteins (Atgs) are required for the formation of the autophagosome and they are highly conserved in Eukaryotes. Among these Atg proteins are the autophagy protein Atg8 and its homologs, which are ubiquitously expressed in all tissues. An upregulation of Atg8 proteins can be observed under various stress conditions (Shpilka,2011). After its translation, the carboxy-terminal region of Atg8 is cleaved in order to expose a glycine residue. Atg8 is then processed by a ubiquitin-like conjugation machinery, which directly conjugates it with its exposed glycine to a PE lipid. This enables Atg8 to be involved both in cargo recruitment into autophagosomes and the formation and elongation of the autophagosome (Johansen,2011).
In contrast to yeast and other fungal species, which have only a single Atg8 protein (P38182), multicellular animals, plants and some protists have several Atg8 homologues. These can be grouped into two subfamilies: the microtubule-associated protein 1 light-chain 3 (MAP1LC3 or LC3) with its variants LC3A (Q9H492), LC3B (Q9GZQ8) and LC3C (Q9BXW4), with two isoforms of LC3A, and the γ-aminobutyrate receptor-associated proteins including GABARAP (O95166), GABARAPL-1 (Q9H0R8) and GABARAPL-2 (P60520). Proteins binding to the Atg8 protein family contain a short hydrophobic LC3-interacting region (LIR), which is often referred to as Atg8-family interacting motif (AIM) in yeast. The LIR is required for these proteins to bind Atg8 and its homologues. Proteins containing LIR motifs include cargo receptors, members of the basal autophagy apparatus, proteins associated with vesicles and of their transport, Rab GTPase-activating proteins (GAPs) and specific signaling proteins that are degraded by selective autophagy. They represent an essential part of autophagosome formation, transport and maturation (Birgisdottir,2013).
Proteins belonging to the Atg8 family have a C-terminal ubiquitin-like (UBL) core, which contains a common ubiquitin-like fold consisting of a four-stranded β-sheet wrapped around a central α-helix. The hydrophobic residues of the central α-helix and the β-strand 2 of the UBL core form a hydrophobic pocket (HP2). Preceding the UBL core is an N-terminal arm with two α-helices. This N-terminal subdomain varies among the different Atg8 subfamilies. It is packed onto the core UBL and forms another deep hydrophobic pocket (HP1) (2KWC) (Kumeta,2010). The LIR docking site is located at the interface of the UBL core and the N-terminal arm and consists of the two hydrophobic pockets HP1 and HP2.
o 6 selected references:

o 5 GO-Terms:

o 21 Instances for LIG_LIR_Gen_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q12983 BNIP3
82 86 QEESLQGSWVELHFSNNGNG TP 5 Homo sapiens (Human)
135 139 EDSPLLEDWDIISPKDVIGS TP 4 Homo sapiens (Human)
P27797 CALR
199 203 ESGSLEDDWDFLPPKKIKDP TP 4 Homo sapiens (Human)
177 181 SSGSSEDSFVEIRMAEGEAE TP 13 Homo sapiens (Human)
7 11 MDAATLTYDTLRFAEFEDFP TP 2 Homo sapiens (Human)
Q13501 SQSTM1
335 341 DNCSGGDDDWTHLSSKEVDP TP 13 Homo sapiens (Human)
P40344 ATG3
269 273 QELDGVGDWEDLQDDIDDSL TP 4 Saccharomyces cerevisiae S288c
P35193 ATG19
411 415 SISLSYDGDDNEKALTWEEL TP 4 Saccharomyces cerevisiae S288c
Q14596 NBR1
730 735 SQSSASSEDYIIILPECFDT TP 6 Homo sapiens (Human)
Q00610 CLTC
511 517 AKKVGYTPDWIFLLRNVMRI TP 3 Homo sapiens (Human)
Q92609 TBC1D5
784 790 SPDDDSSKDSGFTIVSPLDI TP 5 Homo sapiens (Human)
Q92609 TBC1D5
58 62 TFNSYRKEWEELFVNNNYLA TP 5 Homo sapiens (Human)
Q8MQJ7 Atg1
389 394 CSSHEDSDDFVLVPKNLPED TP 3 Drosophila melanogaster (Fruit fly)
1277 1283 DYRPPDDAVFDIITDEELCQ TP 3 Homo sapiens (Human)
O60238 BNIP3L
35 39 PPAGLNSSWVELPMNSSNGN TP 6 Homo sapiens (Human)
P40458 ATG32
85 89 VNDSISGSWQAIQPLDLGAS TP 3 Saccharomyces cerevisiae S288c
P06821 M
88 94 KEQQSAVDADDGHFVSIELE TP 5 Influenza A virus (A/Puerto Rico/8/1934(H1N1))
701 705 SIDAHTFDFETIPHPNIEQT TP 3 Homo sapiens (Human)
351 356 KNSSCDTDDFVLVPHNISSD TP 1 Homo sapiens (Human)
O75385 ULK1
356 360 DSSCDTDDFVMVPAQFPGDL TP 6 Homo sapiens (Human)
O75143 ATG13
442 447 GSSGNTHDDFVMIDFKPAFS TP 5 Homo sapiens (Human)
Please cite: ELM — the eukaryotic linear motif resource in 2020. (PMID:31680160)

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