Fang Li
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455; email: lifang@umn.edu Annu. Rev. Virol. 2016. 3:237–61 First published online as a Review in Advance on August 25, 2016 The Annual Review of Virology is online at virology.annualreviews.org
This article’s doi: 10.1146/annurev-virology-110615-042301
Copyright c 2016 by Annual Reviews.
All rights reserved Keywords:
coronavirus spike protein,
prefusion conformation,
postfusion conformation,
receptor binding, membrane fusion,
virus origin, #
virus evolution
Abstract:
The coronavirus spike protein is a multifunctional molecular machine that mediates coronavirus entry into host cells. It first binds to a receptor on the host cell surface through its S1 subunit and then fuses viral and host membranes through its S2 subunit. Two domains in S1 from different coronaviruses recognize a variety of host receptors, leading to viral attachment. The spike protein exists in two structurally distinct conformations, prefusion and postfusion. The transition from prefusion to postfusion conformation of the spike protein must be triggered, leading to membrane fusion.
This article reviews current knowledge about the structures and functions of coronavirus spike proteins, illustrating how the two S1 domains recognize different receptors and how the spike proteins are regulated to undergo conformational transitions. I further discuss the evolution of these two critical functions of coronavirus spike proteins, receptor recognition and membrane fusion, in the context of the corresponding functions from other viruses and host cells. 237 Click here to view this article's online features: • Download figures as PPT slides • Navigate linked references • Download citations • Explore related articles • Search keywords ANNUAL REVIEWS Further Annu. Rev. Virol. 2016.3:237-261. Downloaded from www.annualreviews.org Access provided by 2601:602:9d00:db10:e9f8:b6ea:3646:b5b6 on 07/18/20. For personal use only. VI03CH11-Li ARI 16 September 2016 9:45 INTRODUCTION Coronaviruses pose serious health threats to humans and other animals. From 2002 to 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) infected 8,000 people, with a fatality rate of ∼10% (1–4). Since 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has infected more than 1,700 people, with a fatality rate of ∼36% (5, 6). Since 2013, porcine epidemic diarrhea coronavirus (PEDV) has swept throughout the United States, causing an almost 100% fatality rate in piglets and wiping out more than 10% of America’s pig population in less than a year (7–9). In general, coronaviruses cause widespread respiratory, gastrointestinal, and central nervous system diseases in humans and other animals, threatening human health and causing economic loss (10, 11). Coronaviruses are capable of adapting to new environments through mutation and recombination with relative ease and hence are programmed to alter host range and tissue tropism efficiently (12–14). Therefore, health threats from coronaviruses are constant and long-term. Understanding the virology of coronaviruses and controlling their spread have important implications for global health and economic stability. Coronaviruses belong to the family Coronaviridae in the order Nidovirales (10, 11). They can be classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus (Figure 1a). Among them, alpha- and betacoronaviruses infect mammals, gammacoronaviruses infect avian species, and deltacoronaviruses infect both mammalian and avian species. Representative alphacoronaviruses include human coronavirus NL63 (HCoV-NL63), porcine transmissible gastroenteritis coronavirus (TGEV), PEDV, and porcine respiratory coronavirus (PRCV). Representative betacoronaviruses include SARS-CoV, MERS-CoV, bat coronavirus HKU4, mouse hepatitis coronavirus (MHV), bovine coronavirus (BCoV), and human coronavirus OC43. Representative gamma- and deltacoronaviruses include avian infectious bronchitis coronavirus (IBV) and porcine deltacoronavirus (PdCV), respectively. Coronaviruses are large, enveloped, positive-stranded RNA viruses. They have the largest genome among all RNA viruses, typically ranging from 27 to 32 kb. The genome is packed inside a helical capsid formed by the nucleocapsid protein (N) and further surrounded by an envelope. Associated with the viral envelope are at least three structural proteins: The membrane protein (M) and the envelope protein (E) are involved in virus assembly, whereas the spike protein (S) mediates virus entry into host cells. Some coronaviruses also encode an envelope-associated hemagglutinin-esterase protein (HE). Among these structural proteins, the spike forms large protrusions from the virus surface, giving coronaviruses the appearance of having crowns (hence their name; corona in Latin means crown) (Figures 1b and 2a). In addition to mediating virus entry, the spike is a critical determinant of viral host range and tissue tropism and a major inducer of host immune responses. The coronavirus spike contains three segments: a large ectodomain, a single-pass transmembrane anchor, and a short intracellular tail (Figure 1b,c). The ectodomain consists of a receptor-binding subunit S1 and a membrane-fusion subunit S2. Electron microscopy studies revealed that the spike is a clove-shaped trimer with three S1 heads and a trimeric S2 stalk (15–18) (Figures 1b and 2a). During virus entry, S1 binds to a receptor on the host cell surface for viral attachment, and S2 fuses the host and viral membranes, allowing viral genomes to enter host cells. Receptor binding and membrane fusion are the initial and critical steps in the coronavirus infection cycle; they also serve as primary targets for human inventions. In this article, I review the structure and function of coronavirus spikes and discuss their evolution.
INTRODUCTION :
Coronaviruses pose serious health threats to humans and other animals. From 2002 to 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) infected 8,000 people, with a fatality rate of ∼10% (1–4). Since 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has infected more than 1,700 people, with a fatality rate of ∼36% (5, 6). Since 2013, porcine epidemic diarrhea coronavirus (PEDV) has swept throughout the United States, causing an almost 100% fatality rate in piglets and wiping out more than 10% of America’s pig population in less than a year (7–9). In general, coronaviruses cause widespread respiratory, gastrointestinal, and central nervous system diseases in humans and other animals, threatening human health and causing economic loss (10, 11). Coronaviruses are capable of adapting to new environments through mutation and recombination with relative ease and hence are programmed to alter host range and tissue tropism efficiently (12–14). Therefore, health threats from coronaviruses are constant and long-term. Understanding the virology of coronaviruses and controlling their spread have important implications for global health and economic stability. Coronaviruses belong to the family Coronaviridae in the order Nidovirales (10, 11). They can be classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus (Figure 1a). Among them, alpha- and betacoronaviruses infect mammals, gammacoronaviruses infect avian species, and deltacoronaviruses infect both mammalian and avian species. Representative alphacoronaviruses include human coronavirus NL63 (HCoV-NL63), porcine transmissible gastroenteritis coronavirus (TGEV), PEDV, and porcine respiratory coronavirus (PRCV). Representative betacoronaviruses include SARS-CoV, MERS-CoV, bat coronavirus HKU4, mouse hepatitis coronavirus (MHV), bovine coronavirus (BCoV), and human coronavirus OC43. Representative gamma- and deltacoronaviruses include avian infectious bronchitis coronavirus (IBV) and porcine deltacoronavirus (PdCV), respectively. Coronaviruses are large, enveloped, positive-stranded RNA viruses. They have the largest genome among all RNA viruses, typically ranging from 27 to 32 kb. The genome is packed inside a helical capsid formed by the nucleocapsid protein (N) and further surrounded by an envelope. Associated with the viral envelope are at least three structural proteins: The membrane protein (M) and the envelope protein (E) are involved in virus assembly, whereas the spike protein (S) mediates virus entry into host cells. Some coronaviruses also encode an envelope-associated hemagglutinin-esterase protein (HE). Among these structural proteins, the spike forms large protrusions from the virus surface, giving coronaviruses the appearance of having crowns (hence their name; corona in Latin means crown) (Figures 1b and 2a). In addition to mediating virus entry, the spike is a critical determinant of viral host range and tissue tropism and a major inducer of host immune responses. The coronavirus spike contains three segments: a large ectodomain, a single-pass transmembrane anchor, and a short intracellular tail (Figure 1b,c). The ectodomain consists of a receptor-binding subunit S1 and a membrane-fusion subunit S2. Electron microscopy studies revealed that the spike is a clove-shaped trimer with three S1 heads and a trimeric S2 stalk (15–18) (Figures 1b and 2a). During virus entry, S1 binds to a receptor on the host cell surface for viral attachment, and S2 fuses the host and viral membranes, allowing viral genomes to enter host cells. Receptor binding and membrane fusion are the initial and critical steps in the coronavirus infection cycle; they also serve as primary targets for human inventions. In this article, I review the structure and function of coronavirus spikes and discuss their evolution.
RECEPTOR RECOGNITION BY CORONAVIRUS SPIKE PROTEINS :
Coronaviruses demonstrate a complex pattern for receptor recognition (19) (Figure 1d ). For example, the alphacoronavirus HCoV-NL63 and the betacoronavirus SARS-CoV both recognize a 238 Li Annu. Rev. Virol. 2016.3:237-261. Downloaded from www.annualreviews.org Access provided by 2601:602:9d00:db10:e9f8:b6ea:3646:b5b6 on 07/18/20. For personal use only. VI03CH11-Li ARI 16 September 2016 9:45 S2 c SARS-CoV MERS-CoV/HKU4 MHV BCoV/OC43 IBV HCoV-NL63 Alphacoronavirus TGEV/PEDV Betacoronavirus Gammacoronavirus PRCV Coronaviridae PdCV Deltacoronavirus S1 S2 TM IC b a d Binds sugar Binds CEACAM1 Binds sugar Binds DPP4 Binds sugar Binds APN Binds APN S1-NTD S1-CTD FP HR-N HR-C S1 S1/S2 TM IC Binds ACE2 Binds ACE2 Viral envelope S2' Figure 1 Introduction to coronaviruses and their spike proteins. (a) Classification of coronaviruses. Representative coronaviruses in each genus are human coronavirus NL63 (HCoV-NL63), porcine transmissible gastroenteritis coronavirus (TGEV), porcine epidemic diarrhea coronavirus (PEDV ), and porcine respiratory coronavirus (PRCV) in the genus Alphacoronavirus; severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), bat coronavirus HKU4, mouse hepatitis coronavirus (MHV), bovine coronavirus (BCoV), and human coronavirus OC43 in the genus Betacoronavirus; avian infectious bronchitis coronavirus (IBV) in the genus Gammacoronavirus; and porcine deltacoronavirus (PdCV) in the genus Deltacoronavirus. (b) Schematic of the overall structure of prefusion coronavirus spikes. Shown are the receptor-binding subunit S1, the membrane-fusion subunit S2, the transmembrane anchor (TM), the intracellular tail (IC), and the viral envelope. (c) Schematic of the domain structure of coronavirus spikes, including the S1 N-terminal domain (S1-NTD), the S1 C-terminal domain (S1-CTD), the fusion peptide (FP), and heptad repeat regions N and C (HR-N and HR-C). Scissors indicate two proteolysis sites in coronavirus spikes. (d ) Summary of the structures and functions of coronavirus spikes. Host receptors recognized by either of the S1 domains are angiotensin-converting enzyme 2 (ACE2), aminopeptidase N (APN), dipeptidyl peptidase 4 (DPP4), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), and sugar. The available crystal structures of S1 domains and S2 HRs are shown. Their PDB IDs are 3KBH for HCoV-NL63 S1-CTD, 4F5C for PRCV S1-CTD, 2AJF for SARS-CoV S1-CTD, 4KR0 for MERS-CoV S1-CTD, 3R4D for MHV S1-NTD, 4H14 for BCoV S1-NTD, 2IEQ for HCoV-NL63 HRs, 1WYY for SARS-CoV HRs, 4NJL for MERS-CoV HRs, and 1WDF for MHV HRs. www.annualreviews.org • Coronavirus Receptor Recognition and Cell Entry 239 Annu. Rev. Virol. 2016.3:237-261. Downloaded from www.annualreviews.org Access provided by 2601:602:9d00:db10:e9f8:b6ea:3646:b5b6 on 07/18/20. For personal use only. VI03CH11-Li ARI 16 September 2016 9:45 a S1-CTD S1-NTD HR-N FP b S1/S2 S2' Figure 2 Cryo–electron microscopy structures of prefusion trimeric coronavirus spikes. (a) Trimeric mouse hepatitis coronavirus (MHV) spike (PDB ID: 3JCL) (16). Three monomers are shown (magenta, cyan, and green). (b) One monomer from the trimeric MHV spike. The important functional elements of the spike [the S1 N-terminal domain (S1-NTD), the S1 C-terminal domain (S1-CTD), the fusion peptide (FP), and the heptad repeat (HR-N)] are colored in the same way as in Figure 1c. The dotted curve indicates a disordered loop. Scissors indicate two critical proteolysis sites. zinc peptidase angiotensin-converting enzyme 2 (ACE2) (20, 21). Moreover, HCoV-NL63 and other alphacoronaviruses recognize different receptors: other alphacoronaviruses such as TGEV, PEDV, and PRCV recognize another zinc peptidase, aminopeptidase N (APN) (22–25). Similarly, SARS-CoV and other betacoronaviruses recognize different receptors: MERS-CoV and HKU4 recognize a serine peptidase, dipeptidyl peptidase 4 (DPP4) (26, 27); MHV recognizes a cell adhesion molecule, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (28, 29); BCoV and OC43 recognize sugar (30). The alphacoronaviruses TGEV and PEDV and the gammacoronavirus IBV also use sugar as receptors or coreceptors (23, 31–34). Other than their role in viral attachment, these coronavirus receptors have their own physiological functions (35–41). The diversity of receptor usage is an outstanding feature of coronaviruses. To further compound the complexity of the issue, the S1 subunits from different genera share little sequence similarity, whereas those from the same genus have significant sequence similarity (42). Therefore, the following questions have been raised regarding receptor recognition by coronaviruses: (a) How do coronaviruses from different genera recognize the same receptor protein? (b) How do coronaviruses from the same genus recognize different receptor proteins? (c) What is the molecular basis for coronavirus spikes to recognize sugar receptors and function as viral lectins? Two major domains in coronavirus S1, N-terminal domain (S1-NTD) and C-terminal domain (S1-CTD), have been identified (Figure 1c,d ). One or both of these S1 domains potentially bind receptors and function as the receptor-binding domain (RBD). S1-NTDs are responsible for binding sugar (23, 34, 43, 44), with the only known exception being betacoronavirus MHV S1-NTD that recognizes a protein receptor CEACAM1 (45). S1-CTDs are responsible for recognizing protein receptors ACE2, APN, and DPP4 (23, 46–51). Crystal structures have been determined for a number of S1 domains complexed with their respective receptor (Figure 1d ). These structures, along with functional studies, have addressed many of the puzzles surrounding receptor recognition by coronaviruses. 240 Li Annu. Rev. Virol. 2016.3:237-261. Downloaded from www.annualreviews.org Access provided by 2601:602:9d00:db10:e9f8:b6ea:3646:b5b6 on 07/18/20. For personal use only. VI03CH11-Li ARI 16 September 2016 9:45
RECEPTOR RECOGNITION BY CORONAVIRUS S1-CTDS:
pike Proteins
pike Proteins
pike Proteins
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