Avian h5 are humans an easy target
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Avian H5: are humans an easy target?. Sinick Group: Signe Christophersen and Nicholas Gauthier Protein Structure and Computational Biology, Spring 2006. Presentation Outline. Introduction to H5 Function Structure H5 Model Quality Validation H1/H5/H9 Comparisons Conclusions

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Avian h5 are humans an easy target
Avian H5: are humans an easy target?

Sinick Group: Signe Christophersen and Nicholas GauthierProtein Structure and Computational Biology, Spring 2006


Presentation outline
Presentation Outline

  • Introduction to H5

    • Function

    • Structure

  • H5 Model

    • Quality Validation

    • H1/H5/H9 Comparisons

  • Conclusions

  • The Uncharacterized Protein

  • Questions?


Introduction h5 function
Introduction – H5 Function

  • Target cell attachment

    • Target receptors consist of sialic acid residues of glycosylated receptor proteins

    • prefers binding α2-6 in humans

    • prefers α2-3 linkage in avian

  • Release of viral contents into the cell

    • Lower pH in endosome causes change in HA that induces fusion of cell and virus membrane

Image taken from (then modified): http://www.ch.ic.ac.uk/local/projects/sanderson/immunology.htm


Introduction h5 structure 1
Introduction – H5 Structure 1

  • Homotrimer of Heterodimers

  • Synthesized in the cell as HA0

  • Trimerizes and is transferred to cell surface


Introduction h5 structure 2
Introduction – H5 Structure 2

  • Proteolytically cleaved to yield HA1 and HA2 which are held together by disulfide bonds

  • HA1 is shown in blue

    • It contains the receptor binding site which is bound to an α2-3 (avian) linkage

  • HA2 is shown in green

    • ~20 residues at the N-terminal are involved in cell/virus fusion


Models of human h5
Models of human H5

  • Has avian H5 adapted to become human specific?

  • Chose newest H5 isolated from human, DQ435202

  • Create models using CPHmodels and HHPred

  • Check quality of template

  • Validate models

  • Differences between H5 found in human and avian


Quality of template
Quality of Template

1JSM was chosen as template for both models

Resolution: 1.9Å

R: 0.234

Rfree: 0.264

  • PROCHECK ramachandran plot

  • Most favoured regions: 84.9

  • Additionally allowed regions: 14.2

  • Generously allowed regions: 0.5

  • Disallowed regions: 0,5


Model validation proq
Model Validation - ProQ

LG > 2.5 very good model

LG > 4 extremely good model

MaxSub > 0.1 fairly good model

MaxSub > 0.8 extremely good model

Template – 1JSM

CPH model

Template – 1JSM

HHPred model



Receptor binding site
Receptor Binding Site

HHPred model

CPH model

Template, 1JSM


Receptor binding site1
Receptor Binding Site

Differences between H5 avian and H5 human isolate

186

193

221


Receptor binding site2
Receptor Binding Site

186

Av – N

Hu - S

193

Av – K

Hu - R

CPH model

Template, 1JSM


Human adaptation how can it happen
Human Adaptation How Can it Happen

  • Avian H1 can become human specific: E190D and G225D

  • Avian H3 can become human specific: Q226L and G228S

  • Mutations introduced into H5 (A/Vietnam/1203/2004)



Avian h5 receptor binding
Avian H5 Receptor binding

E190

Q226

G228

G225


H1 vs h5 receptor binding
H1 vs. H5 Receptor Binding

Differences between H5 (1JSM) and H1 (1RVX)


H1 vs h5 receptor binding1
H1 vs. H5 Receptor Binding

H1 – N193

H5 – K193

H1 – D225

H5 – G225

H1 – P186

H5 – N186

H1, α2-6 receptor, H5, α2-3 receptor


H9 from swine
H9 from swine

α2-6 receptor

α2-3 receptor


H9 vs h5 receptor binding
H9 vs. H5 Receptor Binding

Differences between H5 (1JSM) and H9 (1JSD)


H9 vs h5 receptor binding1
H9 vs. H5 Receptor Binding

H9 – V190

H5 – E190

H9 – L226

H5 – Q226

H1, α2-6

H5, α2-3

H9 – P186

H5 – N186


Conclusion
Conclusion

  • H5 has not been adapted for humans

  • Mutations rendering H5 α2-6 specific have not been identified

  • We propose that human adaptation of H5 might happen via an “H9 pathway”, including the mutations E190V and Q226L. Also, the mutations N186P, L193N and G225D and might play a role.

  • We suggest performing mutational analysis (including these mutations), followed by analyses of receptor binding properties to gain further information of a possible human adaptation of bird flu.


Nonstructural protein 1
Nonstructural Protein 1

  • Structural model created from first 73 residues

    • Structural model created using CPHmodels (shown at right)

    • This domain is suggested to be a nucleic acid binding motif.

  • Last 152 residues had no structural homolog…


Nonstructural protein 1 cont
Nonstructural Protein 1 (cont)

  • Using the remaining 152 residues we…

    • Used HHpred to predict folds (see at right)

    • ProtFun: predicted to be an enzyme (65%), involvement in amino acid biosynthesis (28%)

    • SignalP: no signal peptide, and is non-secretory

    • TMHMM: found no transmembrane regions


Questions
Questions?

Sinick Group: Signe Christophersen and Nicholas GauthierProtein Structure and Computational Biology, Spring 2006


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