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Structural Molecular Insights into SARS Coronavirus Cellular Attachment, Entry and Morphogenesis

ABSTRACT: Coronavirus spikes have the largest mass of any known viral spike molecule. The spike is a type 1 viral fusion protein, a class of trimeric surface glycoprotein proteins from diverse viral families that share many common structural and functional characteristics. Fusion proteins are mainly responsible for host cell receptor recognition and subsequent membrane fusion, and may perform other roles such as virus assembly and release via budding. The conformational changes that occur in the spike of intact SARS coronavirus (SARS-CoV) when it binds to the viral receptor, angiotensin-converting enzyme 2 (ACE2) are described. Clues to the structural/functional relationships of membrane fusion have been made possible by the development of viral purification and inactivation methods, along with cryo-electron microscopy (cryo-EM) and three-dimensional (3D) image processing of many different images containing multiple views of the spikes. These methods have allowed study of the spikes while still attached to virions that are noninfectious, but fusionally competent. The receptor-binding and fusion core domains within the SARS-CoV spike have been precisely localized within the spike. Receptor binding results in structural changes that have been observed in the spike molecule, and these appear to be the initial step in viral membrane fusion. A working model for the stepwise process of receptor binding, and subsequent membrane fusion in SARS-CoV is presented. Uniquely, the large size of the SARS-CoV spike allows structural changes to be observed by cryo-EM in the native state. This provides a useful model for studying the basic process of membrane fusion in general, which forms an essential part of the function of many cellular processes.

SUBMITTER: Beniac D

PROVIDER: S-EPMC7176236 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Middle East respiratory syndrome coronavirus (MERS-CoV) uses the S1B domain of its spike protein to bind to dipeptidyl peptidase 4 (DPP4), its functional receptor, and its S1A domain to bind to sialic acids. The tissue localization of DPP4 in humans, bats, camelids, pigs, and rabbits generally correlates with MERS-CoV tropism, highlighting the role of DPP4 in virus pathogenesis and transmission. However, MERS-CoV S1A does not indiscriminately bind to all ?2,3-sialic acids, and the species-specific binding and tissue distribution of these sialic acids in different MERS-CoV-susceptible species have not been investigated. We established a novel method to detect these sialic acids on tissue sections of various organs of different susceptible species by using nanoparticles displaying multivalent MERS-CoV S1A We found that the nanoparticles specifically bound to the nasal epithelial cells of dromedary camels, type II pneumocytes in human lungs, and the intestinal epithelial cells of common pipistrelle bats. Desialylation by neuraminidase abolished nanoparticle binding and significantly reduced MERS-CoV infection in primary susceptible cells. In contrast, S1A nanoparticles did not bind to the intestinal epithelium of serotine bats and frugivorous bat species, nor did they bind to the nasal epithelium of pigs and rabbits. Both pigs and rabbits have been shown to shed less infectious virus than dromedary camels and do not transmit the virus via either contact or airborne routes. Our results depict species-specific colocalization of MERS-CoV entry and attachment receptors, which may be relevant in the transmission and pathogenesis of MERS-CoV.IMPORTANCE MERS-CoV uses the S1B domain of its spike protein to attach to its host receptor, dipeptidyl peptidase 4 (DPP4). The tissue localization of DPP4 has been mapped in different susceptible species. On the other hand, the S1A domain, the N-terminal domain of this spike protein, preferentially binds to several glycotopes of ?2,3-sialic acids, the attachment factor of MERS-CoV. Here we show, using a novel method, that the S1A domain specifically binds to the nasal epithelium of dromedary camels, alveolar epithelium of humans, and intestinal epithelium of common pipistrelle bats. In contrast, it does not bind to the nasal epithelium of pigs or rabbits, nor does it bind to the intestinal epithelium of serotine bats and frugivorous bat species. This finding supports the importance of the S1A domain in MERS-CoV infection and tropism, suggests its role in transmission, and highlights its potential use as a component of novel vaccine candidates.

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Structural Molecular Insights into SARS Coronavirus Cellular Attachment, Entry and Morphogenesis

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