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:
This non-canonical LIR motif variant exclusively binds to the LC3C homologue of Atg8, which is characterized by its HP2 being less pronounced in comparison to the other Atg8 homologues. As a result, there is a smooth hydrophobic surface instead of two separate hydrophobic pockets. The core motif of this LC3C-specific LIR variant consists of the hydrophobic LVV tripeptide forming an extensive, flat hydrophobic surface. For the three amino acids preceding the core motif, mostly acidic residues and serine or threonine phosphorylation sites are observed, similar to the canonical LIR motif. The LVV tripeptide adopts a beta-strand conformation that interacts with the hydrophobic surface of LC3C and adds an additional beta-strand to the central beta-sheet of the LC3C protein (3VVW) (von Muhlinen,2012). The interaction is further facilitated by electrostatic interactions between acidic residues or serine/threonine phosphorylation sites and basic residues in the N-terminal arm of LC3C (Wild,2013).
Pattern: [EDST].{0,2}LVV
Pattern Probability: 0.0001369
Present in taxon: Eukaryota
Interaction Domain:
Atg8 (PF02991) Autophagy protein Atg8 ubiquitin like (Stochiometry: 1 : 1)
PDB Structure: 3VVW
o See 1 Instance for LIG_LIR_LC3C_4
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 4 selected references:

o 5 GO-Terms:

o 1 Instance for LIG_LIR_LC3C_4
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
132 136 FRPENEEDILVVTTQGEVEE TP 6 Homo sapiens (Human)
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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