The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
Trans-Golgi Network-Endosome-Lysosome-sorting signals
Functional site description:
DxxLL acidic dileucine motifs act as sorting signals between the trans-Golgi network (TGN) and the endosomal-lysosomal compartment. Generally found near the protein C-terminus, they interact with GGA proteins which in turn can recruit clathrin.
ELMs with same func. site: TRG_LysEnd_GGAAcLL_1  TRG_LysEnd_GGAAcLL_2 
ELM Description:
This acidic diLeucine motif is a variant of the TRG_LysEnd_GGAAcLL_1 motif (located near the C-terminus of cargo receptors and binding to VHS domains of GGAs). It is found in the hinge region of GGA1 and GGA3 themselves and binds the N-terminal VHS domains of these GGAs (Doray,2002). It includes an upstream Ser residue which is phosphorylated in vitro by casein kinase 2. The function of GGA 1/3 is regulated by cycles of phosphorylation and dephosphorylation. Phosphorylation induced conformational changes to an "open" state with enhanced binding to GGA 1/3 ligands, because of the release of autoinhibition and enhanced binding to AP1 complex (Ghosh,2003). Strickingly, phosphorylation of the Ser upstream of the TRG_LysEnd_GGAAcLL_1 motif of the cation-independent mannose 6-phosphate receptor enhances its binding to VHS domain of GGAs.
Pattern: S[LW]LD[DE]EL[LM]
Pattern Probability: 2.548e-09
Present in taxon: Coelomata
Interaction Domain:
VHS (PF00790) VHS domain (Stochiometry: 1 : 1)
o See 4 Instances for TRG_LysEnd_GGAAcLL_2
o Abstract
Lysosomes are acidic compartments within cells where lumenal hydrolases degrade endogenous and internalized macromolecules. Most soluble hydrolases transit by the Trans Golgi network (TGN) where they are sorted from secretory proteins before they are directed to the endosome and then the lysosomes.

The trans Golgi network is a major site of membrane protein sorting. The sorting events at the TGN involve transmembrane receptors bearing sorting determinants in their cytoplasmic tails. The interaction of such sorting signals with adaptor proteins such as the GGAs (Golgi-localized, gamma ear-containing, ARF-binding protein) is responsible for the targeting of the receptors (and therefore their cargo). DxxLL acidic diLeucine signals interact with the VHS domains of the GGA adaptor proteins which in turn can bind to clathrin and ARF factor (regulator of coat assembly at the TGN). GGAs act by recruiting the receptors into TGN-derived clathrin-coated vesicles for transport to endosomes. Further sorting to lysosomes or the cell surface may then occur.

The DxxLL acidic diLeucine motifs interacting with GGAs have a very strong preference for Asp at the +1 position. This is in contrast to the acidic diLeucine motifs which bind to the sigma subunit of Adaptin-containing Adapter Protein (AP) complexes also involved in clathrin mediated vesicular transport: The AP complexes have a preference for Glu in the ExxLL acidic dileucine motifs (TRG_DiLeu_BaEn_1).
o 2 selected references:

o 5 GO-Terms:

o 4 Instances for TRG_LysEnd_GGAAcLL_2
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q8BMI3 Gga3
384 391 STNNALSLLDEELLCLGLTD TP 1 Mus musculus (House mouse)
Q8R0H9 Gga1
354 361 QLSASVSLLDDELMSLGLSD TP 2 Mus musculus (House mouse)
388 395 STSNALSWLDEELLCLGLAD TP 7 Homo sapiens (Human)
355 362 QPSASVSLLDDELMSLGLSD TP 7 Homo sapiens (Human)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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