The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
Endosome-Lysosome-Basolateral sorting signals
Functional site description:
Sorting and internalisation signals directing type I transmembrane proteins from the cell surface or TGN to the lysosomal-endosomal compartment. Generally found near the C-terminus, they interact with adaptor protein complexes such as APs and GGAs.
ELMs with same func. site: TRG_LysEnd_APsAcLL_1  TRG_LysEnd_APsAcLL_3  TRG_LysEnd_GGAAcLL_1  TRG_LysEnd_GGAAcLL_2 
ELM Description:
This targeting motif is interacting with the adaptor proteins AP1, AP2, AP3 and probably AP4 achieving internalisation and different levels of sorting within the cell. AP2 is involved in endocytosis at the plasma membrane, AP1 in sorting at the TGN, while AP3 is driving Lysosome/Endosome targeting. AP4 is suspected to be responsible for basolateral targeting. The di Leucine signals are used as signals in all these routes, in combination with other signals (for example Tyrosine based internalisation signals). It is unclear how the specificity for binding to APs is achieved but it seems that the bindign to AP2 is the less specific, allowing any missorted protein to be retrieved by internalisation. Experimental evidence for the specificty for AP binding is not always available, therefore a general pattern can be used to detect all signals of the type D/ExxxLL, and more specific patterns can be used (for AP3 for example, see TRG_LysEnd_APsAcLL_3). Remarkably, a D/ExxxLL motif is used by some virus proteins to be internalised, for ex HIV-1 protein Nef (Craig,1998).
Pattern: [DERQ]...L[LVI]
Pattern Probability: 0.0027577
Present in taxon: Vertebrata
Interaction Domain:
Clat_adaptor_s (PF01217) Clathrin adaptor complex small chain (Stochiometry: 1 : 1)
PDB Structure: 1UJK
o See 16 Instances for TRG_LysEnd_APsAcLL_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 sorting events at the TGN involve transmembrane receptors which are themselves bearing sorting determinants in their cytoplasmic tails.
The interaction of such sorting signals with adaptor proteins such as APs and GGAs is responsible for the targeting of the receptors (and therefore their cargo). The acidic di Leu signals are interacting with the VHS domains of the GGAs adaptor proteins which in turn can bind to clathrin, ARF factor (regulator of coat assembly at the TGN) and other adaptors interacting with AP-1 gamma subunit. GGAs act by recruiting the receptors into TGN-derived clathrin-coated vesicles for transport to endosomes. The juxtamembrane di Leucine signals interact with AP1, AP2, AP3 and probably AP4 in trafficking events such as endocytosis, targeting to lysosomes or specialed compartments like melanosomes.
o 6 selected references:

o 5 GO-Terms:

o 16 Instances for TRG_LysEnd_APsAcLL_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P04601 nef
NEF_HV1H2
160 165 IEEANKGENTSLLHPVSLHG TP 1 HIV-1 M:B_HXB2R
1 
P51519 env
ENV_BLV
463 468 LIKCLTSRLLKLLRQAPHFP TP 2 Bovine leukemia virus
1 
P14142 Slc2a4
GTR4_MOUSE
485 490 QISAAFRRTPSLLEQEVKPS TP 2 Mus musculus (House mouse)
P09693 CD3G
CD3G_HUMAN
149 154 VRQSRASDKQTLLPNDQLYQ TP 1 Homo sapiens (Human)
P01730 CD4
CD4_HUMAN
434 439 RQAERMSQIKRLLSEKKTCQ TP 6 Homo sapiens (Human)
1 
P41143 OPRD1
OPRD_HUMAN
241 246 GLMLLRLRSVRLLSGSKEKD TP 3 Homo sapiens (Human)
1 
P56817 BACE1
BACE1_HUMAN
495 500 CLRCLRQQHDDFADDISLLK TP 1 Homo sapiens (Human)
1 
P16070 CD44
CD44_HUMAN
708 713 GEASKSQEMVHLVNKESSET TP 1 Homo sapiens (Human)
1 
Q04656 ATP7A
ATP7A_HUMAN
1483 1488 SVVTSEPDKHSLLVGDFRED TP 3 Homo sapiens (Human)
1 
P50895 BCAM
BCAM_HUMAN
604 609 HSGSEQPEQTGLLMGGASGG TP 2 Homo sapiens (Human)
1 
P05855 nef
NEF_HV1B8
159 164 KEEANKGENTSLLHPVSLHG TP 5 Human immunodeficiency virus type 1 (BH8 ISOLATE)
1 
O15118 NPC1
NPC1_HUMAN
1271 1276 KSCATEERYKGTERERLLNF TP 2 Homo sapiens (Human)
1 
P06213 INSR
INSR_HUMAN
1021 1026 DEWEVSREKITLLRELGQGS FP 3 Homo sapiens (Human)
P04235 Cd3d
CD3D_MOUSE
138 143 GRPSGAAEVQALLKNEQLYQ TP 2 Mus musculus (House mouse)
1 
P11942 Cd3g
CD3G_MOUSE
149 154 VRQSRASDKQTLLQNEQLYQ TP 6 Mus musculus (House mouse)
1 
P04233 CD74
HG2A_HUMAN
19 24 DQKPVMDDQRDLISNNEQLP TP 4 Homo sapiens (Human)
1 
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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