Hand-foot-and-mouth disease virus receptor KREMEN1 binds the canyon of Coxsackie Virus A10

Abstract

Coxsackievirus A10 (CV-A10) is responsible for an escalating number of severe infections in children, but no prophylactics or therapeutics are currently available. KREMEN1 (KRM1) is the entry receptor for the largest receptor-group of hand-foot-and-mouth disease causing viruses, which includes CV-A10. We report here structures of CV-A10 mature virus alone and in complex with KRM1 as well as of the CV-A10 A-particle. The receptor spans the viral canyon with a large footprint on the virus surface. The footprint has some overlap with that seen for the neonatal Fc receptor complexed with enterovirus E6 but is larger and distinct from that of another enterovirus receptor SCARB2. Reduced occupancy of a particle-stabilising pocket factor in the complexed virus and the presence of both unbound and expanded virus particles suggests receptor binding initiates a cascade of conformational changes that produces expanded particles primed for viral uncoating.

Structural and functional analysis of protective antibodies targeting the threefold plateau of enterovirus 71

“…More than 20 enteroviruses of types A and B, have been reported to cause HFMD. Type A enteroviruses use either SCARB2 or KREMEN1 as entry receptors 36 – 38 , and structures of receptor complexes for both have been determined recently 12 , 39 . SCARB2 binds EV71 on the south rim of the canyon, whilst KREMEN1 engages across the canyon.…”

Serotype specific epitopes identified by neutralizing antibodies underpin immunogenic differences in Enterovirus B

“…5a, b). A number of receptors have been shown to insert themselves inside the viral canyon, whose conserved residues can, therefore, slip under the radar of the immune system, like KREMEN1, FcRn, and CD155 (major receptors for EV-As, EV-Bs, and EV-Cs, respectively) 16,31,[39][40][41] . Unexpectedly, these receptor binding residues are remarkably non-conserved across receptor-dependent viruses 42,43 .…”

Structures of Echovirus 30 in complex with its receptors inform a rational prediction for enterovirus receptor usage

“…A number of receptors have been identified and known to facilitate the entry of EVs, including scavenger receptor B2 (SCARB2; a receptor for EV71, CVA16 and a subgroup of EV-A), Kringlecontaining trans-membrane protein (KREMEN1 for another subgroup of EV-A, including CVA10), coxsackie and adenovirus receptor (CAR; the uncoating receptor for one subgroup of EV-B, including all six serotypes of CVBs), CD55 (the attachment receptor for many EV-Bs), the newly identified Neonatal Fc Receptor (FcRn; the uncoating receptor for another major subgroup of EV-B, containing E30), Intercellular adhesion molecule 1 (ICAM1; the uncoating receptor for one subgroup of EV-C, including CVA21 and CVA24v) and CD155 known as PVR (poliovirus receptor for EV-C) 17,[28][29][30][31][32] . Recently, a number of atomic structures of enteroviruses in complex with their receptors, including EV71, CVA10, E6, PV1 and CVA24v have been characterized 28,[33][34][35][36] . Most of the uncoating receptors bind to the "canyon" sites of the viral particle, dislodging the "pocket factor" in VP1 and subsequently triggering conformational changes of the intact particle to release the genome 28,33,34,[36][37][38][39][40] , albeit that SCARB2 binds EV71 outside the canyon.…”

“…Recently, a number of atomic structures of enteroviruses in complex with their receptors, including EV71, CVA10, E6, PV1 and CVA24v have been characterized 28,[33][34][35][36] . Most of the uncoating receptors bind to the "canyon" sites of the viral particle, dislodging the "pocket factor" in VP1 and subsequently triggering conformational changes of the intact particle to release the genome 28,33,34,[36][37][38][39][40] , albeit that SCARB2 binds EV71 outside the canyon. Receptor usage correlates with the capsid structure, indicative of receptor switching driving viral evolution and subsequent viral classification.…”