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              Researchers Reveal Entry Mechanism of KRM1-dependent Enterovirus A

              Jul 21, 2020

              Recently, Professor GAO Fu (George Fu Gao)’s group at Institute of Microbiology of the Chinese Academy of Sciences uncovered the virus entry mechanism of Enterovirus A by using the two-in-one receptor Kringle containing transmembrane protein 1 (KRM1). The finding was published in PNAS on July 20. 

              Most enteroviruses enter host cells through a two-receptor mechanism, with a first (attachment) receptor to enable virion attaching at the cell surface and a second (uncoating) receptor to trigger conformational changes of viral particle which facilitates the genome release into the cytosol. Some enteroviruses, however, e.g. poliovirus, use only one receptor to accomplish the two steps of cell entry. 

              As a causative agent for hand-foot-and-mouth disease (HFMD), Coxsackievirus A10 (CV-A10) poses great threats to the health of infants and young children worldwide. In addition to the symptoms of HFMD, CV-A10 infection can also lead to a broad range of clinical manifestations, such as fever, herpangina, and even developing viral meningitis. Previous studies have identified KRM1 as an essential receptor for CV-A10 entry, as well as several other enterovirus A species. However, the underlying mechanisms of KRM1-mediated viral entry have not been well understood.

              In this study, Professor GAO’s group presented a comprehensive mechanistic insight into CV-A10 infection using the receptor KRM1.  

              The researchers first found that KRM1 could bind CV-A10 mature virion in both acidic and neutral pH conditions with high affinity, but not the empty viral particles. 

              Then they determined the atomic-resolution structures of CV-A10 alone and its complex with KRM1 at pH 7.4 and pH 5.5 by cryo-EM single particle reconstruction. These structures revealed that KRM1 selectively binds to the mature viral particle above the canyon of viral protein 1 (VP1) subunit and contacts across two adjacent asymmetry units. The key residues for receptor binding are conserved among most KRM1-dependent enteroviruses, suggesting a uniform mechanism for receptor binding. 

              Besides, the binding of KRM1 could induce efficient release of “pocket factor” under acidic conditions and accelerate the conformational change in viral particle to facilitate uncoating. They further reconstituted the uncoating process of CV-A10 by incubating the virion with KRM1 in vitro. 

              The evidence demonstrated that KRM1 is a two-in-one attachment and uncoating receptor for CV-A10 infection, which mediates both viral attachment at the cell surface and uncoating in the endosome. 

              This study expands the understanding on the mechanism of non-enveloped virus infection and indicates new clues for antiviral intervention. 

              The family Picornaviridae represents a group of non-enveloped positive-strand RNA viruses. Within this family, the genus Enterovirus includes many important human pathogens that may cause severe diseases in humans and other mammals, e.g. the common cold, HFMD and poliomyelitis. 

               

              Figure: KRM1 is a two-in-one receptor for CV-A10 entry into the cell (Image by Prof. GAO’s group)

              Contact

              GAO Fu

              Institute of Microbiology

              E-mail:

              Molecular basis of Coxsackievirus A10 entry using the two-in-one attachment and uncoating receptor KRM1

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