Influence of hydrophobic and electrostatic residues on SARS-coronavirus S2 protein stability: insights into mechanisms of general viral fusion and inhibitor design.
Identifieur interne : 001C20 ( Main/Exploration ); précédent : 001C19; suivant : 001C21Influence of hydrophobic and electrostatic residues on SARS-coronavirus S2 protein stability: insights into mechanisms of general viral fusion and inhibitor design.
Auteurs : Halil Aydin [Canada] ; Dina Al-Khooly ; Jeffrey E. LeeSource :
- Protein science : a publication of the Protein Society [ 1469-896X ] ; 2014.
Descripteurs français
- KwdFr :
- Cristallographie aux rayons X, Données de séquences moléculaires, Fusion membranaire, Glycoprotéine de spicule des coronavirus (), Glycoprotéine de spicule des coronavirus (génétique), Humains, Interactions hydrophobes et hydrophiles, Modèles moléculaires, Mutagenèse dirigée, Pénétration virale, Stabilité protéique, Structure tertiaire des protéines, Syndrome respiratoire aigu sévère (virologie), Séquence d'acides aminés, Virus du SRAS (), Virus du SRAS (génétique), Virus du SRAS (physiologie), Électricité statique.
- MESH :
- génétique : Glycoprotéine de spicule des coronavirus, Virus du SRAS.
- physiologie : Virus du SRAS.
- virologie : Syndrome respiratoire aigu sévère.
- Cristallographie aux rayons X, Données de séquences moléculaires, Fusion membranaire, Glycoprotéine de spicule des coronavirus, Humains, Interactions hydrophobes et hydrophiles, Modèles moléculaires, Mutagenèse dirigée, Pénétration virale, Stabilité protéique, Structure tertiaire des protéines, Séquence d'acides aminés, Virus du SRAS, Électricité statique.
English descriptors
- KwdEn :
- Amino Acid Sequence, Crystallography, X-Ray, Humans, Hydrophobic and Hydrophilic Interactions, Membrane Fusion, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Stability, Protein Structure, Tertiary, SARS Virus (chemistry), SARS Virus (genetics), SARS Virus (physiology), Severe Acute Respiratory Syndrome (virology), Spike Glycoprotein, Coronavirus (chemistry), Spike Glycoprotein, Coronavirus (genetics), Static Electricity, Virus Internalization.
- MESH :
- chemical , chemistry : Spike Glycoprotein, Coronavirus.
- chemistry : SARS Virus.
- genetics : SARS Virus, Spike Glycoprotein, Coronavirus.
- physiology : SARS Virus.
- virology : Severe Acute Respiratory Syndrome.
- Amino Acid Sequence, Crystallography, X-Ray, Humans, Hydrophobic and Hydrophilic Interactions, Membrane Fusion, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Stability, Protein Structure, Tertiary, Static Electricity, Virus Internalization.
Abstract
Severe acute respiratory syndrome (SARS) is an acute respiratory disease caused by the SARS-coronavirus (SARS-CoV). SARS-CoV entry is facilitated by the spike protein (S), which consists of an N-terminal domain (S1) responsible for cellular attachment and a C-terminal domain (S2) that mediates viral and host cell membrane fusion. The SARS-CoV S2 is a potential drug target, as peptidomimetics against S2 act as potent fusion inhibitors. In this study, site-directed mutagenesis and thermal stability experiments on electrostatic, hydrophobic, and polar residues to dissect their roles in stabilizing the S2 postfusion conformation was performed. It was shown that unlike the pH-independent retroviral fusion proteins, SARS-CoV S2 is stable over a wide pH range, supporting its ability to fuse at both the plasma membrane and endosome. A comprehensive SARS-CoV S2 analysis showed that specific hydrophobic positions at the C-terminal end of the HR2, rather than electrostatics are critical for fusion protein stabilization. Disruption of the conserved C-terminal hydrophobic residues destabilized the fusion core and reduced the melting temperature by 30°C. The importance of the C-terminal hydrophobic residues led us to identify a 42-residue substructure on the central core that is structurally conserved in all existing CoV S2 fusion proteins (root mean squared deviation=0.4 Å). This is the first study to identify such a conserved substructure and likely represents a common foundation to facilitate viral fusion. We have discussed the role of key residues in the design of fusion inhibitors and the potential of the substructure as a general target for the development of novel therapeutics against CoV infections.
DOI: 10.1002/pro.2442
PubMed: 24519901
Affiliations:
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Lee</name></author></analytic><series><title level="j">Protein science : a publication of the Protein Society</title><idno type="eISSN">1469-896X</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Crystallography, X-Ray</term><term>Humans</term><term>Hydrophobic and Hydrophilic Interactions</term><term>Membrane Fusion</term><term>Models, Molecular</term><term>Molecular Sequence Data</term><term>Mutagenesis, Site-Directed</term><term>Protein Stability</term><term>Protein Structure, Tertiary</term><term>SARS Virus (chemistry)</term><term>SARS Virus (genetics)</term><term>SARS Virus (physiology)</term><term>Severe Acute Respiratory Syndrome (virology)</term><term>Spike Glycoprotein, Coronavirus (chemistry)</term><term>Spike Glycoprotein, Coronavirus (genetics)</term><term>Static Electricity</term><term>Virus Internalization</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Cristallographie aux rayons X</term><term>Données de séquences moléculaires</term><term>Fusion membranaire</term><term>Glycoprotéine de spicule des coronavirus ()</term><term>Glycoprotéine de spicule des coronavirus (génétique)</term><term>Humains</term><term>Interactions hydrophobes et hydrophiles</term><term>Modèles moléculaires</term><term>Mutagenèse dirigée</term><term>Pénétration virale</term><term>Stabilité protéique</term><term>Structure tertiaire des protéines</term><term>Syndrome respiratoire aigu sévère (virologie)</term><term>Séquence d'acides aminés</term><term>Virus du SRAS ()</term><term>Virus du SRAS (génétique)</term><term>Virus du SRAS (physiologie)</term><term>Électricité statique</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Spike Glycoprotein, Coronavirus</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>SARS Virus</term><term>Spike Glycoprotein, Coronavirus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Glycoprotéine de spicule des coronavirus</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Crystallography, X-Ray</term><term>Humans</term><term>Hydrophobic and Hydrophilic Interactions</term><term>Membrane Fusion</term><term>Models, Molecular</term><term>Molecular Sequence Data</term><term>Mutagenesis, Site-Directed</term><term>Protein Stability</term><term>Protein Structure, Tertiary</term><term>Static Electricity</term><term>Virus Internalization</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cristallographie aux rayons X</term><term>Données de séquences moléculaires</term><term>Fusion membranaire</term><term>Glycoprotéine de spicule des coronavirus</term><term>Humains</term><term>Interactions hydrophobes et hydrophiles</term><term>Modèles moléculaires</term><term>Mutagenèse dirigée</term><term>Pénétration virale</term><term>Stabilité protéique</term><term>Structure tertiaire des protéines</term><term>Séquence d'acides aminés</term><term>Virus du SRAS</term><term>Électricité statique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Severe acute respiratory syndrome (SARS) is an acute respiratory disease caused by the SARS-coronavirus (SARS-CoV). SARS-CoV entry is facilitated by the spike protein (S), which consists of an N-terminal domain (S1) responsible for cellular attachment and a C-terminal domain (S2) that mediates viral and host cell membrane fusion. The SARS-CoV S2 is a potential drug target, as peptidomimetics against S2 act as potent fusion inhibitors. In this study, site-directed mutagenesis and thermal stability experiments on electrostatic, hydrophobic, and polar residues to dissect their roles in stabilizing the S2 postfusion conformation was performed. It was shown that unlike the pH-independent retroviral fusion proteins, SARS-CoV S2 is stable over a wide pH range, supporting its ability to fuse at both the plasma membrane and endosome. A comprehensive SARS-CoV S2 analysis showed that specific hydrophobic positions at the C-terminal end of the HR2, rather than electrostatics are critical for fusion protein stabilization. Disruption of the conserved C-terminal hydrophobic residues destabilized the fusion core and reduced the melting temperature by 30°C. The importance of the C-terminal hydrophobic residues led us to identify a 42-residue substructure on the central core that is structurally conserved in all existing CoV S2 fusion proteins (root mean squared deviation=0.4 Å). This is the first study to identify such a conserved substructure and likely represents a common foundation to facilitate viral fusion. We have discussed the role of key residues in the design of fusion inhibitors and the potential of the substructure as a general target for the development of novel therapeutics against CoV infections.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><noCountry><name sortKey="Al Khooly, Dina" sort="Al Khooly, Dina" uniqKey="Al Khooly D" first="Dina" last="Al-Khooly">Dina Al-Khooly</name><name sortKey="Lee, Jeffrey E" sort="Lee, Jeffrey E" uniqKey="Lee J" first="Jeffrey E" last="Lee">Jeffrey E. Lee</name></noCountry><country name="Canada"><region name="Ontario"><name sortKey="Aydin, Halil" sort="Aydin, Halil" uniqKey="Aydin H" first="Halil" last="Aydin">Halil Aydin</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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