High-efficiency utilization of the bovine integrin alpha(v)beta(3) as a receptor for foot-and-mouth disease virus is dependent on the bovine beta(3) subunit

We have previously reported that Foot-and-morcth disease virus (FMDV), whic h is virulent For cattle and swine, can utilize the integrin alpha(nu)beta( 3) as a receptor on cultured cells. Since those studies were performed with the human integrin, we have molecularly cloned the bovine homolog of the i ntegrin alpha(nu)beta(3) and have compared the two receptors for utilizatio n by FMDV, Both the alpha(nu) and beta(3) subunits of the bovine integrin h ave high degrees of amino acid sequence similarity to their corresponding h uman subunits in the ectodomains (96%) and essentially identical transmembr ane and cytoplasmic domains. Within the putative ligand-binding domains, th e bovine and human alpha(nu) subunits have a 98.8% amino acid sequence simi larity while there is only a 93% similarity between the beta(3) subunits of these two species, COS cell cultures, which are not susceptible to FMDV in fection, become susceptible if cotransfected with alpha(nu) and beta(3) sub unit cDNAs from a bovine or human source. Cultures cotransfected with the b ovine alpha(nu)beta(3) subunit cDNAs and infected with FMDV synthesize grea ter amounts of viral proteins than do infected cultures cotransfected with the human integrin subunits. Cells cotransfected with a bovine alpha(nu) su bunit and a human beta(3) subunit synthesize viral proteins at levels equiv alent to those in cells expressing both human subunits, However, cells cotr ansfected with the human alpha(nu) and the bovine beta(3) subunits synthesi ze amounts of viral proteins equivalent to those in cells expressing both b ovine subunits, indicating that the bovine beta(3) subunit is responsible f or the increased effectiveness of this receptor. By engineering chimeric bo vine-human beta(3) subunits, we have shown that this increase in receptor e fficiency is due to sequences encoding the C-terminal one-third of the subu nit ectodomain, which contains a highly structured cysteine-rich repeat reg ion. We postulate that amino acid sequence differences within this region m ay be responsible for structural differences between the human and bovine b eta(3) subunit, leading to more efficient utilization of the bovine recepto r by this bovine pathogen.