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. 2013 Oct 10:10:304.
doi: 10.1186/1743-422X-10-304.

Adaptive evolution of bat dipeptidyl peptidase 4 (dpp4): implications for the origin and emergence of Middle East respiratory syndrome coronavirus

Jie Cui  1 , John-Sebastian Eden, Edward C Holmes, Lin-Fa Wang
Affiliations

Adaptive evolution of bat dipeptidyl peptidase 4 (dpp4): implications for the origin and emergence of Middle East respiratory syndrome coronavirus

Jie Cui et al. Virol J. .

Abstract

Background: The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) that first appeared in Saudi Arabia during the summer of 2012 has to date (20th September 2013) caused 58 human deaths. MERS-CoV utilizes the dipeptidyl peptidase 4 (DPP4) host cell receptor, and analysis of the long-term interaction between virus and receptor provides key information on the evolutionary events that lead to the viral emergence.

Findings: We show that bat DPP4 genes have been subject to significant adaptive evolution, suggestive of a long-term arms-race between bats and MERS related CoVs. In particular, we identify three positively selected residues in DPP4 that directly interact with the viral surface glycoprotein.

Conclusions: Our study suggests that the evolutionary lineage leading to MERS-CoV may have circulated in bats for a substantial time period.

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Figures

Figure 1
Figure 1
Selection pressures on DPP4 during mammalian evolution. Ratios of nonsynonymous (dN) to synonymous (dS) nucleotide substitutions per site (dN/dS) are shown on four major ancestral branches; dN and dS numbers are also given in parentheses. Values for individual lineages are given in Table 2. DPP4 sequences of bat origin are shaded.
Figure 2
Figure 2
Interaction of bat DPP4 and MERS-CoV spike protein receptor-binding domain and the location of positively selected sites. The structure was displayed using PyMol v1.6 (http://www.pymol.org/). (A) Homology model showing the structural interactions between bat DPP4 (from common pipistrelle) coloured grey and MERS-CoV spike protein receptor-binding domain coloured blue. The three positively selected residues (positions 187, 288 and 392) located within the interface where the virus-host interact are highlighted as red. (B) Protein alignment of human DPP4 compared to that of seven bat species showing RBD spanning codons 41 – 400. Conserved and variable positions are shown in black and grey text, respectively, and residues under positive selection are coloured red.
See this image and copyright information in PMC

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