lxxll

LxxLL is a short linear motif defined by the amino acid sequence leucine–any amino acid–any amino acid–leucine–leucine (LxxLL). It functions as a nuclear receptor box found in a broad class of transcriptional coactivators that augment hormone receptor signaling. The motif is typically embedded in coactivator proteins and contributes to the formation of transcriptional activation complexes.

Mechanistically, the LxxLL motif binds to the ligand-binding domain of nuclear receptors. Binding is often ligand-dependent; when a receptor is activated, a hydrophobic groove on the receptor’s AF-2 surface recognizes the LxxLL-containing helix of the coactivator. This interaction helps recruit additional transcriptional machinery and supports ligand-dependent gene activation.

Occurrence and examples: The motif is common in steroid receptor coactivators, notably members of the p160/SRC family such as SRC-1 (NCOA1), TIF2 (NCOA2), and SRC-3 (NCOA3). It is also found in other coactivators and regulatory proteins. While the exact surrounding sequence can vary, the conserved feature is the two leucines at the end of the motif.

Significance and use in research: The LxxLL–nuclear receptor interaction is central to many hormone-responsive gene programs. Researchers frequently use synthetic peptides containing LxxLL sequences to disrupt NR–coactivator interactions or to map binding interfaces, and mutating the motif often reduces binding affinity and transcriptional activation.

History: The concept of the NR box and the LxxLL motif emerged in the 1990s with the identification of coactivator regions that interact with nuclear receptor LBDs, highlighting a key mechanism of transcriptional regulation by nuclear receptors.