The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
di Lysine ER retrieving signal
Functional site description:
Located at the C-terminus of ER type I membrane proteins (cytoplasmic in this topology), interacts with members of the coatomer (COPI).
ELM Description:
ER retention and retrieving signal found at the C-terminus of type I ER membrane proteins (cytoplasmic in this topology). Di-Lysine signal is responsible for COPI-mediated retrieval from post-ER compartments.
Pattern: K.{0,1}K.{2,3}$
Pattern Probability: 0.0000268
Present in taxon: Eukaryota
Interaction Domain:
WD40 (PF00400) WD domain, G-beta repeat (Stochiometry: 1 : 1)
o See 14 Instances for TRG_ER_diLys_1
o Abstract
The di-Lysine motif is found in type I membrane proteins of the ER and interacts directly with COPI (gamma-COP), which then drives the recycling of type I membrane proteins to the ER. Experimental data suggest that di-Lysine results in an enrichment in the intermediate compartment and cis-Golgi, while KDEL (TRG_ER_KDEL_1) dictates residency in the ER.
The di-Lysine motif has to be exposed from the membrane lipids in order to function: a minimum of 5 amino acid residues is probably required between the first charged residue of the cytoplasmic tail and the first Lysine of the motif. The di-lysine motif appears to be conserved across eukaryotes, and mutagenesis studies show remarkable conservation of the functional motif between yeast and human. Some substitutions of Lysine by Arginine are permitted. Although the di-Lysine motif is the minimum requirement for targeting, the sequences flanking the Lysines can influence retention efficiency.
STERIC MASKING: the list of proteins that possess a di-Lysine motif contains several proteins known to be localized in their mature folded state at the cell surface. An example is the mouse T-cell receptor beta-chain or high affinity IgE receptor alpha-chain. An explanation was provided by the observation that the motif on the alpha-chain can be sterically masked by polypeptides from the gamma-chain of the receptor. As a result the di-Lysine motif became non functional after the alpha-chain correctly assemble with the gamma-chain thereby ensuring that only functional complexes exit the ER.
o 6 selected references:

o 17 GO-Terms:

o 14 Instances for TRG_ER_diLys_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P78381 SLC35A2
392 396 RGDLITEPFLPKLLTKVKGS TP 2 Homo sapiens (Human)
P11223 S
1159 1162 YYTTFDNDVVTEQYRPKKSV TP 2 Avian infectious bronchitis virus (strain Beaudette)
P59635 7a
156 159 TLLYLKYKSRRSFIDEKKMP TP 4 Human adenovirus 2
Q91841 Translocon-as
201 205 LATWQVCYLRHFFKAKKLIE TP 1 Xenopus laevis (African clawed frog)
232 235 AIGVWQMRHLKSFFEAKKLV TP 6 Homo sapiens (Human)
P49755 TMED10
215 219 LATWQVFYLRRFFKAKKLIE TP 6 Homo sapiens (Human)
P33767 WBP1
427 430 VSFVTTSSVGKKLETFKKTN TP 7 Saccharomyces cerevisiae (Baker"s yeast)
P43555 EMP47
441 445 LVMAYYTFRIRQEIIKTKLL TP 7 Saccharomyces cerevisiae (Baker"s yeast)
P12371 Fcer1a
242 245 HKQFESILKIQKTGKGKKKG TP 1 Rattus norvegicus (Norway rat)
P04035 HMGCR
885 888 HNRSKINLQDLQGACTKKTA TP 4 Homo sapiens (Human)
P22309 UGT1A1
529 533 YRKCLGKKGRVKKAHKSKTH TP 4 Homo sapiens (Human)
P49257 LMAN1
507 510 LFIGYIMYRSQQEAAAKKFF TP 3 Homo sapiens (Human)
Q40235 Cf-9
860 863 MDLKLEHIITTKMKKHKKRY TP 7 Solanum pimpinellifolium
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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