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:
Sorting signal located at the C-terminus of type I transmembrane proteins from the Trans Golgi Network (TGN) targeted to the lysosomal-endosomal compartment. It interacts with the VHS domain of GGAs adaptor proteins, allowing the incorporation of cargo receptors and their cargo into clathrin coated vesicles budding from the TGN. Phosphorylation of a Serine residue upstream of the motif by casein kinase 2 could regulate the recognition of the motif at the TGN. It has been demonstrated that for the cation dependent mannose 6-phosphate receptor, phosphorylation of this Ser enhances the binding of the signal to its recognition module, the VHS domain of GGAs, by creating an additional point of attcahment to it (Kato,2002).
Pattern: D..LL.{1,2}$
Pattern Probability: 9.585e-07
Present in taxons: Bos taurus Coelomata Gallus gallus Homo sapiens Mus musculus Rattus norvegicus Xenopus laevis
Interaction Domain:
VHS (PF00790) VHS domain (Stochiometry: 1 : 1)
PDB Structure: 1LF8
o See 6 Instances for TRG_LysEnd_GGAAcLL_1
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 5 selected references:

o 6 GO-Terms:

o 6 Instances for TRG_LysEnd_GGAAcLL_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P11717 IGF2R
2485 2491 VSSTKLVSFHDDSDEDLLHI TP 8 Homo sapiens (Human)
P08169 IGF2R
2493 2499 AAATPISTFHDDSDEDLLHV TP 1 Bos taurus (Cattle)
O75074 LRP3
764 770 PPPPCSPMLEASDDEALLVC TP 2 Homo sapiens (Human)
Q99523 SORT1
826 831 TASHTNKSGYHDDSDEDLLE TP 4 Homo sapiens (Human)
P11456 M6PR
273 279 VGDDQLGEESEERDDHLLPM TP 3 Bos taurus (Cattle)
P20645 M6PR
271 277 VGDDQLGEESEERDDHLLPM TP 11 Homo sapiens (Human)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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