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.

SH3 domains: modules of protein–protein interactions

“…The attempt to compensate for this shortcoming of low specificity of SH3 domains was made for GRB2 by designing a dimeric peptide recognizing a dimeric SH3 domain. Other candidates for anticancer treatment based on high-affinity peptides that bind the SH3 domain include the Crk adaptor (Feller and Lewitzky 2006) and the Grb2 and Crk SH2/SH3 (Kardinal et al 1999;Kadaveru et al 2009). Further elucidation of the structure and function of SH3 domains interacting with their partners and the development of new peptide-based drug design approaches will facilitate the exploration of these important protein modular interaction domains as drug targets.…”

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

“…41,42 Predicting binding sites by sequence matches to the motifs of ELMs, 34,35 LMs, 36 SLiMs, 37,38 or other collections of sequence patterns [43][44][45] provides one strategy for identifying potential binding sites located within IDPs or IDP regions. Using sequence characteristics that indicate short binding regions within longer regions of disorder offers a second strategy that does not depend on specific motifs, and several predictors have been developed that use this second strategy.…”

Norovirus RNA-Dependent RNA Polymerase Is Phosphorylated by an Important Survival Kinase, Akt

“…Therefore, the viral RNA-dependent RNA polymerase (RdRp) is likely to play an important role in driving viral evolution and fitness (6). Posttranslational modifications of viral proteins (15), including RdRps (17), are frequently found, and this led us to examine a potential posttranslational modification of such a polymerase from a representative pandemic NoV strain, GII.4 2006b (NSW696T/06/AU-GenBank EF684915). This variant was associated with a global pandemic in 2007 to 2008 (23) and caused three consecutive epidemics of gastroenteritis in Australia in 2006 (26), 2007, and 2008 (12).…”