TIM-1 acts a dual-attachment receptor for Ebolavirus by interacting directly with viral GP and the PS on the viral envelope

Yuan, Shuai; Cao, Lei; Ling, Hui; Dang, Minghao; Sun, Yao; Zhang, Xuyuan; Chen, Yutao; Zhang, Liguo; Su, Dan; Wang, Xiangxi; Rao, Zihe

doi:10.1007/s13238-015-0220-y

Cited by 41 publications

(59 citation statements)

References 41 publications

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“…The structures of mTIM-1 and -4 and hTIM-1 and -4 IgV domains have been solved, showing that residues of the CC= and FG loops that are important for PtdSer binding make up the PtdSer binding pocket (25,26,28,29). Using those structures, as well as a linear sequence alignment, we summarize the mTIM-4 and hTIM-4 IgV domain residues important for filovirus entry and compare those residues to hTIM-1 IgV domain residues previously found to be important (12) (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study by Yuan et al suggests that hTIM-1 interacts not only with virion-associated PtdSer but also with the EBOV GP to facilitate cellular virus entry (28). This recent observation stands in contrast to a series of other studies providing evidence that TIM proteins interact not with EBOV GP but solely with PtdSer on the virion (12,13,29).…”

Section: Igv Domain Residues Near the Upper Loop Of The Ptdser Bindinmentioning

confidence: 93%

“…However, the sequence of the CC= loop that forms the bottom of the PtdSer binding pocket was not as highly conserved between mTIM-4 and hTIM-4. Next, we aligned the structures of the mTIM-4 IgV domain and the recently elucidated hTIM-4 IgV domain (25,28). In general, the hTIM-4 and mTIM-4 IgV structures were similar (Fig.…”

Section: Expression Of Htim-4 and Mtim-4 Enhances Filovirus Entrymentioning

confidence: 95%

“…While both domains are required for EBOV internalization into cells (24), virion-associated PtdSer is thought to interact directly with residues within the IgV domain (12). The structures of all of the mTIM and hTIM IgV domains have been solved (25)(26)(27)(28)(29). While the IgV domains from different TIMs are similar, they are not identical, with differences in structure found between TIM homologs, as well as between the murine and human orthologs.…”

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confidence: 99%

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Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry

Rhein

Brouillette

Schaack

et al. 2016

J Virol

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Phosphatidylserine (PtdSer) receptors that are responsible for the clearance of dying cells have recently been found to mediate enveloped virus entry. Ebola virus (EBOV), a member of the Filoviridae family of viruses, utilizes PtdSer receptors for entry into target cells. The PtdSer receptors human and murine T-cell immunoglobulin mucin (TIM) domain proteins TIM-1 and TIM-4 mediate filovirus entry by binding to PtdSer on the virion surface via a conserved PtdSer binding pocket within the amino-terminal IgV domain. While the residues within the TIM-1 IgV domain that are important for EBOV entry are characterized, the molecular details of virion-TIM-4 interactions have yet to be investigated. As sequences and structural alignments of the TIM proteins suggest distinct differences in the TIM-1 and TIM-4 IgV domain structures, we sought to characterize TIM-4 IgV domain residues required for EBOV entry. Using vesicular stomatitis virus pseudovirions bearing EBOV glycoprotein (EBOV GP/ VSV⌬G), we evaluated virus binding and entry into cells expressing TIM-4 molecules mutated within the IgV domain, allowing us to identify residues important for entry. Similar to TIM-1, residues in the PtdSer binding pocket of murine and human TIM-4 (mTIM-4 and hTIM-4) were found to be important for EBOV entry. However, additional TIM-4-specific residues were also found to impact EBOV entry, with a total of 8 mTIM-4 and 14 hTIM-4 IgV domain residues being critical for virion binding and internalization. Together, these findings provide a greater understanding of the interaction of TIM-4 with EBOV virions. IMPORTANCEWith more than 28,000 cases and over 11,000 deaths during the largest and most recent Ebola virus (EBOV) outbreak, there has been increased emphasis on the development of therapeutics against filoviruses. Many therapies under investigation target EBOV cell entry. T-cell immunoglobulin mucin (TIM) domain proteins are cell surface factors important for the entry of many enveloped viruses, including EBOV. TIM family member TIM-4 is expressed on macrophages and dendritic cells, which are early cellular targets during EBOV infection. Here, we performed a mutagenesis screening of the IgV domain of murine and human TIM-4 to identify residues that are critical for EBOV entry. Surprisingly, we identified more human than murine TIM-4 IgV domain residues that are required for EBOV entry. Defining the TIM IgV residues needed for EBOV entry clarifies the virus-receptor interactions and paves the way for the development of novel therapeutics targeting virus binding to this cell surface receptor. Ebolavirus and Marburgvirus, members of the Filoviridae family, are enveloped, negative-sense RNA viruses that cause severe hemorrhagic fever in humans and nonhuman primates. A member of the Ebolavirus genus, Ebola virus (EBOV), is a causative agent of episodic filovirus outbreaks in Africa, including the most recent and deadly West African epidemic that began in December 2013 (1, 2). Contributing to the virulent nature of this virus is the ...

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Section: Discussionmentioning

confidence: 99%

Section: Igv Domain Residues Near the Upper Loop Of The Ptdser Bindinmentioning

confidence: 93%

Section: Expression Of Htim-4 and Mtim-4 Enhances Filovirus Entrymentioning

confidence: 95%

mentioning

confidence: 99%

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Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry

Rhein

Brouillette

Schaack

et al. 2016

J Virol

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“…Indeed, the structure provided no clues as to where T-cell Ig and mucin 1 (TIM-1), the proposed receptor (10,11), might attach. In addition, the virus capsid contains no pocket factor and can withstand remarkably high temperature and low pH, indicating an uncoating mechanism (7) unlike that of enteroviruses; heating of HAV particles does not transform virions to an expanded state in vitro.…”

mentioning

confidence: 99%

Potent neutralization of hepatitis A virus reveals a receptor mimic mechanism and the receptor recognition site

Wang

Zhu

Dang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Hepatitis A virus (HAV) infects ∼1.4 million people annually and, although there is a vaccine, there are no licensed therapeutic drugs. HAV is unusually stable (making disinfection problematic) and little is known of how it enters cells and releases its RNA. Here we report a potent HAV-specific monoclonal antibody, R10, which neutralizes HAV infection by blocking attachment to the host cell. High-resolution cryo-EM structures of HAV full and empty particles and of the complex of HAV with R10 Fab reveal the atomic details of antibody binding and point to a receptor recognition site at the pentamer interface. These results, together with our observation that the R10 Fab destabilizes the capsid, suggest the use of a receptor mimic mechanism to neutralize virus infection, providing new opportunities for therapeutic intervention.picornavirus | entry | neutralizing mechanism | receptor recognition | uncoating H epatitis A virus (HAV) is an ancient and ubiquitous pathogen found in primates and small mammals (1). It is a picornavirus with many distinctive features: in the blood it is found in an enveloped form but is shed in feces as a naked, unenveloped particle (2); it possesses a low G/C ratio in the genome sequence and a strong codon bias (3); it grows poorly in tissue culture; it possesses a 67-residue carboxyl-terminal extension of VP1 (VP1-2A or VPX), which is important for viral assembly (4); and it has a very short, nonmyristoylated VP4 (∼23 residues) (5). Because of its unusual properties, HAV remains enigmatic and occupies an evolutionary position on the periphery of picornaviruses (6, 7).Our previous crystal structure of unenveloped HAV (7) showed no trace of the canyon that encircles the fivefold axes of enteroviruses and is often the site of receptor binding (8, 9). Indeed, the structure provided no clues as to where T-cell Ig and mucin 1 (TIM-1), the proposed receptor (10, 11), might attach. In addition, the virus capsid contains no pocket factor and can withstand remarkably high temperature and low pH, indicating an uncoating mechanism (7) unlike that of enteroviruses; heating of HAV particles does not transform virions to an expanded state in vitro. Structural characterization of a HAV-TIM-1 complex might elucidate the cell-entry mechanism, but difficulty in obtaining homogenous complex preparations because of the low binding affinity of TIM-1, at least for unenveloped particles, has made this challenging. However, it is known that neutralizing antibodies (NAbs) protect against virus infection by mechanisms that include blocking attachment to the cellular receptor, overstabilizing the virus, preventing viral genome release, or physically destabilizing the virus (12, 13). Structural studies of virus complexes with such antibodies can therefore help illuminate these underlying biological functions. Here we identify a highly potent Nab, R10, which can neutralize HAV infection efficiently by blocking attachment to the host cell. The complex structure of the HAV full particle and R10 Fab suggest where the re...

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Molecularly Imprinted Polymer Nanogels for Protein Recognition: Direct Proof of Specific Binding Sites by Solution STD and WaterLOGSY NMR Spectroscopies

et al. 2021

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Molecularly imprinted polymers (MIPs) are tailor‐made synthetic antibodies possessing specific binding cavities designed for a target molecule. Currently, MIPs for protein targets are synthesized by imprinting a short surface‐exposed fragment of the protein, called epitope or antigenic determinant. However, finding the epitope par excellence that will yield a peptide “synthetic antibody” cross‐reacting exclusively with the protein from which it is derived, is not easy. We propose a computer‐based rational approach to unambiguously identify the “best” epitope candidate. Then, using Saturation Transfer Difference (STD) and WaterLOGSY NMR spectroscopies, we prove the existence of specific binding sites created by the imprinting of this peptide epitope in the MIP nanogel. The optimized MIP nanogel could bind the epitope and cognate protein with a high affinity and selectivity. The study was performed on Hepatitis A Virus Cell Receptor‐1 protein, also known as KIM‐1 and TIM‐1, for its ubiquitous implication in numerous pathologies.

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TIM-1 acts a dual-attachment receptor for Ebolavirus by interacting directly with viral GP and the PS on the viral envelope

Cited by 41 publications

References 41 publications

Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry

Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry

Potent neutralization of hepatitis A virus reveals a receptor mimic mechanism and the receptor recognition site

Molecularly Imprinted Polymer Nanogels for Protein Recognition: Direct Proof of Specific Binding Sites by Solution STD and WaterLOGSY NMR Spectroscopies

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