Abstract

The di-Lysine motif is beared by type I membrane proteins of the ER,
it interacts directly with COPI (gamma-COP), which then drives the recycling of type I membrane proteins to the ER. Experimental evidences suggest that di-Lysine results in an enrichment in the intermediate compartment and cis-Golgi while KDEL 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 aa 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 humans.
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.