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Proteins that permanently reside in the lumen of the endoplasmic reticulum (ER) seem to be distinguished from newly synthesized secretory proteins by the presence of the C-terminal sequence Lys-Asp-Glu-Leu (KDEL) [1,2]. While KDEL is the preferred signal in many species, variants of that signal are used by different species. This situation is described in the following table.

   Signal   Species
   ----------------------------------------------------------------
   KDEL     Vertebrates, Drosophila, Caenorhabditis elegans, plants
   HDEL     Saccharomyces cerevisiae, Kluyveromyces lactis, plants
   DDEL     Kluyveromyces lactis
   ADEL     Schizosaccharomyces pombe (fission yeast)
   SDEL     Plasmodium falciparum

The signal is usually very strictly conserved in major ER proteins but some minor ER proteins have divergent sequences (probably because efficient retention of these proteins is not crucial to the cell).

Proteins bearing the KDEL-type signal are not simply held in the ER, but are selectively retrieved from a post-ER compartment by a receptor and returned to their normal location.

The currently known ER luminal proteins are listed below.

• Protein disulfide-isomerase (PDI) (also known as the β-subunit of prolyl 4-hydroxylase, as a component of oligosaccharyl transferase, as glutathione-insulin transhydrogenase and as a thyroid hormone binding protein).
• ERp60, ERp72, and P5, three minor isoforms of PDI.
• Trypanosoma brucei bloodstream-specific protein 2, a probable PDI.
• hsp70 related protein GRP78 (also known as the immunoglobulin heavy chain binding protein (BiP), and as KAR2, in fungi).
• hsp90 related protein 'endoplasmin' (also known as GRP94, Erp99 or Hsp108).
• Calreticulin, a calcium-binding protein (also known as calregulin, CRP55, or HACBP).
• ERC-55, a calcium-binding protein.
• Reticulocalbin, a calcium-binding protein.
• Hsp47, a heat-shock protein that binds strongly to collagen and could act as a chaperone in the collagen biosynthetic pathway.
• A receptor for a plant hormone, auxin.
• Thiol proteases from rice bean (SH-EP) and kidney bean (EP-C1).
• Esterases from mammalian liver and from nematodes.
• α-2-macroglobulin receptor-associated protein (RAP).
• Yeast peptidyl-prolyl cis-trans isomerase D (CYPD).
• Yeast protein KRE5, a protein required for (1->6)-β-D-glucan synthesis.
• Yeast protein SEC20, required for the transport of proteins from the endoplasmic reticulum to the Golgi apparatus.
• Yeast protein SCJ1, involved in protein sorting.

November 1997 / Text revised.

PROSITE method (with tools and information) covered by this documentation:

ER_TARGET, PS00014; Endoplasmic reticulum targeting sequence  (PATTERN)

Consensus pattern: [KRHQSA]-[DENQ]-E-L> Sequences known to belong to this class detected by the pattern: ALL, except for liver esterases which have H-[TVI]-E-L Other sequence(s) detected in Swiss-Prot: 24 proteins which are clearly not located in the ER (because they are of bacterial or viral origin, for example) and a protein which can be considered as valid candidate: human 80K- H protein

• Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS00014 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS00014 • Scan Swiss-Prot/TrEMBL entries against PS00014 • view ligand binding statistics

Matching PDB structures: 1G7D 2DIZ 2FTU 2P01 ... [ALL]

1	Authors	Munro S., Pelham H.R.B.
	Title	A C-terminal signal prevents secretion of luminal ER proteins.
	Source	Cell 48:899-907(1987).
	PubMed ID	3545499

2	Authors	Pelham H.R.B.
	Title	The retention signal for soluble proteins of the endoplasmic reticulum.
	Source	Trends Biochem. Sci. 15:483-486(1990).
	PubMed ID	2077689

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