Location of HuPAR2 residues and regions that determine HuPAR2 function identified to date. HuPAR2 (no shading) has two regions involved in its function as a PERV-A receptor. The first N-terminal 135 amino acids contain the absolute requirements for viral receptor function. The role of L109 (open white diamond) as a determinant of PERV-A SU binding was confirmed. Residues T5, D40, P73, Q82, H110, L119 and T127 (black circles), identified by MuPAR/HuPAR2 chimeras, contribute to the efficiency of HuPAR2 function and are found in multiple structural elements. The second region (a.a. 152–285), identified by HuPAR1/HuPAR2 chimeras, determines the enhanced efficiency of HuPAR2 function for PERV-A infection. This region spans the third extracellular loop, sixth transmembrane domain, third intracellular loop and seventh transmembrane domain.