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Structural Determinants of Tissue Tropism and In Vivo Pathogenicity for the Parvovirus Minute Virus of Mice

Maria Kontou,^1, Lakshmanan Govindasamy,¹ Hyun-Joo Nam,¹ Nathan Bryant,¹ Antonio L. Llamas-Saiz,^2, Concepción Foces-Foces,² Eva Hernando,^3, Mari-Paz Rubio,^3,¶ Robert McKenna,¹ José M. Almendral,³ and Mavis Agbandje-McKenna^1*

Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida 32610-0245,¹ Departamento de Cristalografia, Instituto de Quimica-Fisica "Rocasolano," CSIC, Serrano 119, 28006 Madrid,² Centro de Biologia Molecular "Severo Ochoa" (UAM-CSIC), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain³

Received 11 March 2005/ Accepted 25 May 2005

Two strains of the parvovirus minute virus of mice (MVM), the immunosuppressive (MVMi) and the prototype (MVMp) strains, display disparate in vitro tropism and in vivo pathogenicity. We report the crystal structures of MVMp virus-like particles (MVMp_b) and native wild-type (wt) empty capsids (MVMp_e), determined and refined to 3.25 and 3.75 Å resolution, respectively, and their comparison to the structure of MVMi, also refined to 3.5 Å resolution in this study. A comparison of the MVMp_b and MVMp_e capsids showed their structures to be the same, providing structural verification that some heterologously expressed parvovirus capsids are indistinguishable from wt capsids produced in host cells. The structures of MVMi and MVMp capsids were almost identical, but local surface conformational differences clustered from symmetry-related capsid proteins at three specific domains: (i) the icosahedral fivefold axis, (ii) the "shoulder" of the protrusion at the icosahedral threefold axis, and (iii) the area surrounding the depression at the icosahedral twofold axis. The latter two domains contain important determinants of MVM in vitro tropism (residues 317 and 321) and forward mutation residues (residues 399, 460, 553, and 558) conferring fibrotropism on MVMi. Furthermore, these structural differences between the MVM strains colocalize with tropism and pathogenicity determinants mapped for other autonomous parvovirus capsids, highlighting the importance of common parvovirus capsid regions in the control of virus-host interactions.

Present address: University of Thessaly, Argonafton and Filellinon, 38221 Volos, Greece.

Present address: Unidade de Raios X. RIAIDT, Vicerrectorado de Investigación, Universidade de Santiago de Compostela, E-15706, Santiago de Compostela, Spain.

Present address: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

^¶ Present address: Instituto de Biomedicina de Valencia (CSIC), 46010 Valencia, Spain.

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