The Bunyaviridae virus family is a large and diverse family of human, animal and plant pathogens responsible for many medically and economically important diseases throughout the world. The Rift Valley fever virus (RVFV) is a bunyavirus from the phlebovirus genus and consider to be a new emerging human and animal pathogen. Bunyaviruses have an outer lipid envelope bearing two glycoproteins, GN and GC, required for cell entry. Bunyaviruses deliver their genome into the host-cell cytoplasm by fusing their envelope with an endosomal membrane. Although RVFV and other bunyaviruses have been studied for nearly a century, there is lack in high-resolution structural information for their entry process. Our crystal structure of RVFV GC reveals a class II fusion protein architecture found previously only in flaviviruses and alphaviruses. The structure identifies GC as the effector of membrane fusion and provides a direct view of the membrane anchor that initiates fusion. A structure of non-glycosylated GC reveals an extended conformation that may represent a fusion intermediate. Unanticipated similarities between GC and flavivirus envelope proteins reveal an evolutionary link between the two virus families and provide insights on the organization of GC in the outer shell of RVFV and the virion assembly.
