RGD is the single letter code for arginine-glycine-aspartate. This tripeptide motif can be found in proteins of the extracellular matrix. Integrins link the intracellular cytoskeleton of cells with the extracellular matrix by recognizing this RGD motif. Without attachment to the extracellular matrix, cells normally undergo apoptosis ('anoikis'). Soluble RGD peptides induce apoptosis and might be used as drugs against angiogenesis, inflammation and cancer mestastasis since small soluble peptides containing the RGD motif inhibit cell attachment and consequently induce apoptosis.
Interestingly, caspase-3 contains a RGD sequence near its active site, and additionally a putative RGD binding site (aspartate-aspartate-methionine, DDM). It was proposed that pro-caspase-3 keeps itself inactive by the intramolecular interaction between its RGD and DDM sites. RGD peptides might block this interaction, and pro-caspase-3 would be able to be activated. RGD peptides might be naturally formed when extracellular matrix proteins are degraded and cause apoptosis of cells in involuting tissues. Moreover, the Tat protein of HIV-1 contains a RGD motif within its sequence and might be responsible for apoptosis- induction in even uninfected bystander lymphocytes because Tat is rapidly internalized by cells. On the other hand, Apaf-1/CED-4 contains five DDX sites (RGD-binding motif) within its WD40 repeats which are supposed to be involved in protein-protein interaction and another DDX site in a region essential for CED-4 oligomerization and subsequent apoptosis! (Buckley et al., 1999, Nature, 397: 534-39).