Viral infection and human disease--insights from minimotifs

Abstract

Short functional peptide motifs cooperate in many molecular functions including protein interactions, protein trafficking, and posttranslational modifications. Viruses exploit these motifs as a principal mechanism for hijacking cells and many motifs are necessary for the viral life-cycle. A virus can accommodate many short motifs in its small genome size providing a plethora of ways for the virus to acquire host molecular machinery. Host enzymes that act on motifs such as kinases, proteases, and lipidation enzymes, as well as protein interaction domains, are commonly mutated in human disease, suggesting that the short peptide motif targets of these enzymes may also be mutated in disease; however, this is not observed. How can we explain why viruses have evolved to be so dependent on motifs, yet these motifs, in general do not seem to be as necessary for human viability? We propose that short motifs are used at the system level. This system architecture allows viruses to exploit a motif, whereas the viability of the host is not affected by mutation of a single motif.

Figure 1

Chemical structures of FDA-approved motif mimetic drugs. Comparisons of the chemical structures of small compounds (Morphine and Aggrastat® (Tirofiban)) to the peptide motifs they mimic (Enkephalins and RGD Integrin ligands), respectively. The R group in Enkephalins can be Met for Met-enkaphalin, Leu for Leu-enkephalin, or other peptide for longer Enkephalin peptides such as β-endorphin.