YxxLI

YxxLI is a short linear motif described in the cytoplasmic tails of certain transmembrane proteins. It represents a variant of the well-known tyrosine-based sorting motif YxxØ, where Y is tyrosine, x is any residue, and Ø is a bulky hydrophobic residue. In the YxxLI variant, the sequence matches tyrosine followed by any two residues and then leucine (L) and isoleucine (I). The motif is implicated in trafficking signals that can mediate recognition by clathrin adaptor protein complexes (such as AP-1, AP-2, and AP-3) and the assembly of clathrin-coated vesicles, thereby influencing endocytosis and intracellular sorting.

Function and context: Recognition of YxxLI is context-dependent. Binding to adaptor complexes can promote internalization from the plasma membrane or sorting at the trans-Golgi network and endosomes. The efficiency and outcome of recognition depend on surrounding residues and the structural environment of the cargo protein; substitutions at the Y position or at the L/I positions often disrupt trafficking.

Occurrence and examples: YxxLI is not universal but has been reported in a subset of cargo proteins and regulatory receptors. Some viral proteins and cellular regulators may utilize YxxLI- or Yxxφ-like motifs to hijack or modulate host trafficking pathways, illustrating the motif’s functional versatility.

Research and methods: Identification typically involves sequence analysis to detect the motif, followed by mutational studies (for example, Y to F substitutions) and trafficking assays, complemented by biochemical binding studies with AP subunits.

See also: tyrosine-based sorting motif; YxxØ; clathrin-mediated endocytosis; adaptor protein complexes.