Transplanted LDL and mannose-6-phosphate receptor internalization signals promote high-efficiency endocytosis of the transferrin receptor.
The internalization signals of several constitutively recycling receptors have recently been identified as regions of four or six amino acids that include an aromatic residue, usually tyrosine. Here, we show that transplanted signals from the low density lipoprotein receptor (LDLR) and cation-independent mannose-6-phosphate receptor (Man-6-PR) promote rapid internalization of the transferrin receptor (TR), directly establishing that recognition signals are interchangeable, self-determined structural motifs and that signals from type I membrane proteins are active in a type II receptor. We also show that the chemical and spatial patterns of critical residues in both four- and six-residue internalization motifs are consistent with a tight turn structure. A six-residue LDLR signal is needed for activity in TR, suggesting that an amino-terminal aromatic side chain is obligatory. In contrast, the carboxy-terminal aromatic side chain in the TR signal can be replaced by a large hydrophobic residue. Thus, internalization signals apparently require an aromatic amino-terminal residue and either an aromatic or large hydrophobic carboxy-terminal residue rather than a conserved tyrosine per se. Consistent with this conclusion, predicted internalization signals from the poly-Ig receptor, YSAF, and asialoglycoprotein receptor (ASGPR) subunit H1, YQDL, also promote internalization of TR.
Collawn
J F
JF
Department of Cancer Biology, Salk Institute, San Diego, CA 92186-5800.
Kuhn
L A
LA
Liu
L F
LF
Tainer
J A
JA
Trowbridge
I S
IS
D000595:Amino Acid Sequence; D037263:Asialoglycoprotein Receptor; D004705:Endocytosis; D006801:Humans; D007501:Iron / Q000378:metabolism; D008360:Mannosephosphates / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D014168:Transferrin / Q000378:metabolism
D037263:Asialoglycoprotein Receptor; D008360:Mannosephosphates; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D011990:Receptors, Transferrin; D014168:Transferrin; D007501:Iron