Architectural organization and fusion protein structure of lymphocytic choriomeningitis virus.

UNLABELLED

Arenaviruses exist globally and can cause hemorrhagic fever and neurological diseases, exemplified by the zoonotic pathogen lymphocytic choriomeningitis virus (LCMV). The structures of individual LCMV proteins or their fragments have been reported, but the architectural organization and the nucleocapsid assembly mechanism remain elusive. Importantly, the structure of the arenavirus fusion protein complex (glycoprotein complex, GPC) as present on the virion prior to fusion, particularly with its integral stable signal peptide (SSP), has not been shown, hindering efforts such as structure-based vaccine design. Here, we have determined the structure of LCMV proteins and their architectural organization in the virion by cryogenic electron tomography. The tomograms reveal the global distribution of GPC, matrix protein Z, and the contact points between the viral envelope and nucleocapsid. Subtomogram averaging yielded the structure of the mature GPC with its transmembrane domain intact, revealing the GP2-SSP interface and the endodomain of GP2. The number of RNA-dependent RNA polymerase L molecules packaged within each virion varies, adding new perspectives to the infection mechanism. Together, these results delineate the structural organization of LCMV and offer new insights into its mechanism of LCMV maturation, egress, and cell entry.

IMPORTANCE

The impact of COVID-19 on public health has highlighted the importance of understanding zoonotic pathogens. Lymphocytic choriomeningitis virus (LCMV) is a rodent-borne human pathogen that causes hemorrhagic fever. Herein, we describe the structure of LCMV proteins and their architectural organization on the viral envelope and around the nucleocapsid. The virion structure reveals the distribution of the surface glycoprotein complex (GPC) and the contact points between the viral envelope and the underlying matrix protein, as well as the association with the nucleocapsid. The morphology and sizes of virions, as well as the number of RNA polymerase L inside each virion vary greatly, highlighting the fast-changing nature of LCMV. A comparison between the GPC trimeric structure and prior ectodomain structures identifies the transmembrane and endo domains of GPC and key interactions among its subunits. The work provides new insights into LCMV assembly and informs future structure-guided vaccine design.