The NPXY internalization signal of the LDL receptor adopts a reverse-turn conformation

Abstract

Peptides corresponding to the proposed coated pit internalization signal of the native low density lipoprotein receptor, NPVY, take up in aqueous solution a reverse-turn conformation with the Asn in position i and the Tyr in position i + 3. By contrast, peptides derived from receptors that are defective for endocytosis do not adopt the reverse turn. These internalization-defective receptors include those with a nonaromatic residue substituted for the Tyr and those with Asn→Ala or Pro→Ala substitutions. While the tendency of an Asn-Pro sequence to induce a reverse turn was anticipated, the structural importance of an aromatic residue in position i + 3 was not. The sequences associated with the internalization signal thus appear to play a critical conformational role that is required for endocytosis, probably by enabling binding to adaptor molecules. With the results presented in the accompanying paper on lysosomal acid phosphatase, we now have direct evidence for previous proposals of a general correlation of internalization signals with a turn conformational motif.