leading to tumorigenesis and when they are targeted by Flavivirus
or IAV protein PBMs they modulate the same signaling pathways
affecting the same cellular processes but the result of the infection is
quite different [52, 61]. This is probably due to the specific cellular
context of each infection, as each of these viruses infects different
cell types, and the effect in each viral infection is unique.
Interestingly, one of the differences between viral and cellular
PBMs is that as viruses evolve faster than the cellular genomes, viral
PBMs may change throughout evolution to adapt to new hosts or
contexts, as has been observed by the incorporation of new PBMs
in SARS-CoV genome when E protein PBM was deleted [66] or
with the changes in PBM core sequences in some SARS-CoV and
MERS-CoV variants isolated from bats [67]. In fact, more than
40 different PBMs were identified in more than 33 CoV genomes
isolated from different hosts, reinforcing the relevance of viral PBMs
in virus adaptation and suggesting that CoVs could be a good model
to study the relevance of viral PBMs in virus evolution. Furthermore,
viral PBMs seem promising targets for antiviral therapy, as small
peptides blocking the interaction of viral PBMs with the cellular
PDZs could be used as antivirals to block virus pathogenicity.
There is still much to be learned about how viral PBMs work.
The field of nononcovirus PBMs is essentially unexplored with the
exception of CoVs. To gain a better understanding on how viral
PBMs influence viral infections, the mechanisms of replication and
pathogenesis induced by the PBMs of nononcogenic viruses such as
CoV, IAV, DENV or RABV need to be further studied. For the
moment, we have shown that the study of the cellular mechanisms
disrupted by human CoV PBMs are highly relevant for a better
understanding of virus–host interaction. Hopefully, this will open
the way to study viral PBMs of other highly pathogenic viruses in
more detail.
References
1. Gerek ZN, Keskin O, Ozkan SB (2009) Identification of specificity and promiscuity of PDZ
domain interactions through their dynamic
behavior. Proteins 77:796–811
2. Kennedy MB (1995) Origin of PDZ (DHR,
GLGF) domains. Trends Biochem Sci 20:350
3. Ponting CP (1997) Evidence for PDZ domains
in bacteria, yeast, and plants. Protein Sci
6:464–468
4. Luck K, Charbonnier S, Trave G (2012) The
emerging contribution of sequence context to
the specificity of protein interactions mediated
by PDZ domains. FEBS Lett 586:2648–2661
5. Nourry C, Grant SG, Borg JP (2003) PDZ
domain proteins: plug and play! Sci STKE
2003:RE7
6. Ye F, Zhang M (2013) Structures and target
recognition modes of PDZ domains: recurring
themes and emerging pictures. Biochem J
455:1–14
7. Subbaiah VK, Kranjec C, Thomas M, Banks L
(2011) PDZ domains: the building blocks regulating
tumorigenesis.
Biochem
J
439:195–205
8. Gallardo R, Ivarsson Y, Schymkowitz J,
Rousseau F, Zimmermann P (2010) Structural
diversity of PDZ-lipid interactions. Chembiochem 11:456–467
232
Carlos Castan ˜ o-Rodriguez et al.
or IAV protein PBMs they modulate the same signaling pathways
affecting the same cellular processes but the result of the infection is
quite different [52, 61]. This is probably due to the specific cellular
context of each infection, as each of these viruses infects different
cell types, and the effect in each viral infection is unique.
Interestingly, one of the differences between viral and cellular
PBMs is that as viruses evolve faster than the cellular genomes, viral
PBMs may change throughout evolution to adapt to new hosts or
contexts, as has been observed by the incorporation of new PBMs
in SARS-CoV genome when E protein PBM was deleted [66] or
with the changes in PBM core sequences in some SARS-CoV and
MERS-CoV variants isolated from bats [67]. In fact, more than
40 different PBMs were identified in more than 33 CoV genomes
isolated from different hosts, reinforcing the relevance of viral PBMs
in virus adaptation and suggesting that CoVs could be a good model
to study the relevance of viral PBMs in virus evolution. Furthermore,
viral PBMs seem promising targets for antiviral therapy, as small
peptides blocking the interaction of viral PBMs with the cellular
PDZs could be used as antivirals to block virus pathogenicity.
There is still much to be learned about how viral PBMs work.
The field of nononcovirus PBMs is essentially unexplored with the
exception of CoVs. To gain a better understanding on how viral
PBMs influence viral infections, the mechanisms of replication and
pathogenesis induced by the PBMs of nononcogenic viruses such as
CoV, IAV, DENV or RABV need to be further studied. For the
moment, we have shown that the study of the cellular mechanisms
disrupted by human CoV PBMs are highly relevant for a better
understanding of virus–host interaction. Hopefully, this will open
the way to study viral PBMs of other highly pathogenic viruses in
more detail.
References
1. Gerek ZN, Keskin O, Ozkan SB (2009) Identification of specificity and promiscuity of PDZ
domain interactions through their dynamic
behavior. Proteins 77:796–811
2. Kennedy MB (1995) Origin of PDZ (DHR,
GLGF) domains. Trends Biochem Sci 20:350
3. Ponting CP (1997) Evidence for PDZ domains
in bacteria, yeast, and plants. Protein Sci
6:464–468
4. Luck K, Charbonnier S, Trave G (2012) The
emerging contribution of sequence context to
the specificity of protein interactions mediated
by PDZ domains. FEBS Lett 586:2648–2661
5. Nourry C, Grant SG, Borg JP (2003) PDZ
domain proteins: plug and play! Sci STKE
2003:RE7
6. Ye F, Zhang M (2013) Structures and target
recognition modes of PDZ domains: recurring
themes and emerging pictures. Biochem J
455:1–14
7. Subbaiah VK, Kranjec C, Thomas M, Banks L
(2011) PDZ domains: the building blocks regulating
tumorigenesis.
Biochem
J
439:195–205
8. Gallardo R, Ivarsson Y, Schymkowitz J,
Rousseau F, Zimmermann P (2010) Structural
diversity of PDZ-lipid interactions. Chembiochem 11:456–467
232
Carlos Castan ˜ o-Rodriguez et al.