How to find a leucine in a haystack? Structure, ligand recognition and regulation of leucine-aspartic acid (LD) motifs

Biochem J. 2014 Jun 15;460(3):317-29. doi: 10.1042/BJ20140298.


LD motifs (leucine-aspartic acid motifs) are short helical protein-protein interaction motifs that have emerged as key players in connecting cell adhesion with cell motility and survival. LD motifs are required for embryogenesis, wound healing and the evolution of multicellularity. LD motifs also play roles in disease, such as in cancer metastasis or viral infection. First described in the paxillin family of scaffolding proteins, LD motifs and similar acidic LXXLL interaction motifs have been discovered in several other proteins, whereas 16 proteins have been reported to contain LDBDs (LD motif-binding domains). Collectively, structural and functional analyses have revealed a surprising multivalency in LD motif interactions and a wide diversity in LDBD architectures. In the present review, we summarize the molecular basis for function, regulation and selectivity of LD motif interactions that has emerged from more than a decade of research. This overview highlights the intricate multi-level regulation and the inherently noisy and heterogeneous nature of signalling through short protein-protein interaction motifs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology
  • Amino Acid Motifs / physiology*
  • Apoptosis Regulatory Proteins / physiology
  • Aspartic Acid / metabolism*
  • Cell Cycle Proteins / physiology
  • Focal Adhesion Kinase 2 / chemistry
  • Humans
  • Leucine / metabolism*
  • Ligands
  • Membrane Proteins / physiology
  • Microfilament Proteins / metabolism
  • Paxillin / chemistry
  • Poly(A)-Binding Protein I / metabolism
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • Vinculin / physiology


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Cell Cycle Proteins
  • GIT1 protein, human
  • Ligands
  • Membrane Proteins
  • Microfilament Proteins
  • PARVA protein, human
  • PDCD10 protein, human
  • Paxillin
  • Poly(A)-Binding Protein I
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • VCL protein, human
  • Vinculin
  • Aspartic Acid
  • Focal Adhesion Kinase 2
  • Leucine