Mycobacterium tuberculosis H37Rv is an intracellular pathogen responsible for causing tuberculosis in humans. The M. tuberculosis genome has been shown to contain a very large and unique family of PE proteins made of two sub-families: PE-only and PE_PGRS proteins. These two subtypes of proteins play a crucial role in the pathogenesis of the microbe. However, despite numerous investigations, the role of these proteins in disease development remains obscure. In this study, sequence analysis with a search for short conserved motifs revealed a conserved tetra-peptide motif DEVS/DXXS at the PE domain of almost every PE-only and PE_PGRS protein. The motif was found at a distance of 43-46 amino acids from the N-terminal of PE_PGRS proteins, and at a distance of between 35 and 82 amino acids of the PE-only proteins. As phosphorylation of the serine residue of this tetra-peptide could yield a motif similar to the caspase-3 binding recognition sequence DEVD/E, the region from a representative PE_PGRS protein (PE_PGRS45) was docked to human caspase-3. Strong interactions of only the protein containing the phosphorylated motif (DEVpS/DXXpS) to caspase-3 were observed. This suggested that the conserved DEVS/DXXS motif could have evolved for phosphorylation and subsequent recognition by caspase-3. These findings have important implications in unravelling the role of these PE proteins in mycobacterial infection.