Disease relevance of Dilysine

• An intact dilysine-like motif in the carboxyl terminus of MAL is required for normal apical transport of the influenza virus hemagglutinin cargo protein in epithelial Madin-Darby canine kidney cells [1].
• Here we demonstrate that the spike (S) protein from the group 3 coronavirus infectious bronchitis virus (IBV) contains a canonical dilysine endoplasmic reticulum retrieval signal (-KKXX-COOH) in its cytoplasmic tail [2].
• We recently identified an endoplasmic reticulum (ER) retrieval signal-the dilysine motif-in the glycoproteins of all five foamy viruses (FVs) for which sequences were available (P. A. Goepfert, G. Wang, and M. J. Mulligan, Cell 82:543-544, 1995) [3].
• When overexpressed in HIV-1-producing cells, HO3 was incorporated into wild-type virions but not in ones containing the dilysine-mutated variant of MA [4].
• We now provide a novel extraneuronal cell model in which human Epstein-Barr virus transformed B cells that constitutively hardly produce APP are transfected with wild-type or mutated APP695, harboring the Swedish mutation APPsw, or a dilysine endoplasmic reticulum retrieval motif--APP(ER) [5].

High impact information on Dilysine

• By contrast, the dilysine retrieval signal, which competes for the same binding site on coatomer, has no effect on GTPase activity [6].
• It is inferred that, in vivo, sorting signal selection is under kinetic control, with coatomer governing a GTPase discard pathway that excludes dilysine-tagged proteins from one class of COPI-coated vesicles [6].
• Coatomer from beta'-COP (sec27-1) and alpha-COP (ret1-1) mutants, but not from gamma-COP (sec21) mutants, had lost the ability to bind dilysine motifs in vitro [7].
• We describe a system to assess retrieval to the ER in yeast cells making use of a dilysine-tagged Ste2 protein [7].
• Coatomer is essential for retrieval of dilysine-tagged proteins to the endoplasmic reticulum [7].

Chemical compound and disease context of Dilysine

• Recently, we identified a dilysine endoplasmic reticulum (ER) retrieval signal and a tyrosine-based endocytosis signal in the cytoplasmic tail of the S protein of infectious bronchitis virus (IBV) [8].

Biological context of Dilysine

• Mutation of a dilysine motif in the beta sandwich core of the domain eliminates endocytosis [9].
• The tomato Cf-9 disease resistance gene encodes a type I membrane protein carrying a cytosolic dilysine motif [10].
• From these results, we conclude that coatomer is able to bind to the cytoplasmic dilysine motifs of membrane proteins of the early secretory pathway via its gamma-COP subunit, whose complete cDNA-derived amino acid sequence is also presented [11].
• Protein targeting to endoplasmic reticulum by dilysine signals involves direct retention in addition to retrieval [12].
• Peptide binding in OppA, the crystal structures of the periplasmic oligopeptide binding protein in the unliganded form and in complex with lysyllysine [13].

Anatomical context of Dilysine

• Coatomer, the major component of the coat of COPI transport vesicles, binds both to the dilysine motif of resident membrane proteins of the endoplasmic reticulum and to the cytoplasmic domain of p23, a major type I membrane protein of COPI vesicles [14].
• In the presence of dilysine, HeLa cells adhere to the apical side of epithelia and to the dorsal side of the upper layer of the blastoderm [15].
• We used connexin constructs containing a C-terminal dilysine-based ER retention/retrieval signal (HKKSL) transfected into HeLa cells to study early events in connexin oligomerization [16].
• Retention of BACE in the endoplasmic reticulum by introduction of a C-terminal dilysine motif prevented complex carbohydrate processing and demonstrated that propeptide cleavage occurs after exit from this organelle [17].
• Vma21p contains a dilysine motif at the carboxy terminus, and mutation of these lysine residues abolishes retention in the endoplasmic reticulum and results in delivery of Vma21p to the vacuole, the default compartment for yeast membrane proteins [18].

Associations of Dilysine with other chemical compounds

• Domains that contained dilysine endoplasmic reticulum retrieval signals bound the alpha-, beta'-, and epsilon-COP subunits of coatomer, whereas other p24 domains bound the beta-, gamma-, and zeta-COP subunits and required a phenylalanine-containing motif [19].
• Significantly, production of APPbeta occurred even when APP was retained in the ER/ intermediate compartment by inhibition with brefeldin A, incubation at 15 degrees C, or by expression of exogenous APP bearing the dilysine ER retrieval motif [20].
• Influx of glycylsarcosine and L-lysyl-L-lysine into hamster jejunum in vitro [21].
• "Mutual" amino acid catalysis of glycine on the formation of ditryptophan, dilysine, and diserine in the prebiotically relevant Salt-Induced Peptide Formation (SIPF) Reaction was investigated varying the starting concentration and chirality of the educt amino acid, and analyzing the increase of yield resulting from this catalytic effect [22].
• The direct superoxide scavenging ability of the tetrahydrochloride dilysine astaxanthin salt was also evaluated by electron paramagnetic resonance (EPR) spectroscopy in a well-characterized in vitro isolated human neutrophil assay [23].

Gene context of Dilysine

• For example, binding of COP1 to dilysine (KKXX) motifs induces specific retrieval of tagged proteins from the Golgi back to the endoplasmic reticulum (ER) [24].
• Binding of beta'-COP to RGS4 occurred through two dilysine motifs in RGS4, similar to those contained in some aminoglycoside antibiotics that are known to bind coatomer [25].
• These results suggest a role for the Sec20/Tip20p complex in retrieval of dilysine-tagged proteins back to the ER [26].
• The Sec20/Tip20p complex is involved in ER retrieval of dilysine-tagged proteins [26].
• Gene deletion experiments of other family members showed that only GLO3 deletion resulted in impaired retrieval of dilysine-tagged proteins back to the ER [27].

Analytical, diagnostic and therapeutic context of Dilysine

• Direct titration of the apo-proteins with anions as well as anion-dependent iron release studies show that the dilysine pair is part of an active anion-binding site which exists with the Lys296-Tyr188 interaction as a core [28].
• We now present additional evidence for this concept, based on autoaggregation studies of plastic beads coated with glycosphingolipids (GSLs) bearing Le(x) or other epitopes, and affinity chromatography on Le(x)-columns of multivalent lactofucopentaose III (Le(x) oligosaccharide) conjugated with lysyllysine [29].

References