Tryptophan-dependent membrane interaction and heteromerization with the internal fusion peptide by the membrane proximal external region of SARS-CoV spike protein.
Identifieur interne : 001208 ( Main/Exploration ); précédent : 001207; suivant : 001209Tryptophan-dependent membrane interaction and heteromerization with the internal fusion peptide by the membrane proximal external region of SARS-CoV spike protein.
Auteurs : Ying Liao ; Si Min Zhang ; Tuan Ling Neo ; James P. TamSource :
- Biochemistry [ 1520-4995 ] ; 2015.
Descripteurs français
- KwdFr :
- Alanine (), Alanine (génétique), Animaux, Cellules Vero, Fragments peptidiques (métabolisme), Glycoprotéine de spicule des coronavirus (), Glycoprotéine de spicule des coronavirus (génétique), Glycoprotéine de spicule des coronavirus (métabolisme), Liaison aux protéines (génétique), Membrane cellulaire (métabolisme), Membrane cellulaire (virologie), Motifs et domaines d'intéraction protéique (génétique), Multimérisation de protéines (génétique), Phénylalanine (), Phénylalanine (génétique), Protéines de fusion virale (), Protéines de fusion virale (génétique), Protéines de fusion virale (métabolisme), Substitution d'acide aminé, Tryptophane (), Tryptophane (physiologie), Virus du SRAS (génétique), Virus du SRAS (métabolisme).
- MESH :
- génétique : Alanine, Glycoprotéine de spicule des coronavirus, Liaison aux protéines, Motifs et domaines d'intéraction protéique, Multimérisation de protéines, Phénylalanine, Protéines de fusion virale, Virus du SRAS.
- métabolisme : Fragments peptidiques, Glycoprotéine de spicule des coronavirus, Membrane cellulaire, Protéines de fusion virale, Virus du SRAS.
- physiologie : Tryptophane.
- virologie : Membrane cellulaire.
- Alanine, Animaux, Cellules Vero, Glycoprotéine de spicule des coronavirus, Phénylalanine, Protéines de fusion virale, Substitution d'acide aminé, Tryptophane.
English descriptors
- KwdEn :
- Alanine (chemistry), Alanine (genetics), Amino Acid Substitution, Animals, Cell Membrane (metabolism), Cell Membrane (virology), Chlorocebus aethiops, Peptide Fragments (metabolism), Phenylalanine (chemistry), Phenylalanine (genetics), Protein Binding (genetics), Protein Interaction Domains and Motifs (genetics), Protein Multimerization (genetics), SARS Virus (genetics), SARS Virus (metabolism), Spike Glycoprotein, Coronavirus (chemistry), Spike Glycoprotein, Coronavirus (genetics), Spike Glycoprotein, Coronavirus (metabolism), Tryptophan (chemistry), Tryptophan (physiology), Vero Cells, Viral Fusion Proteins (chemistry), Viral Fusion Proteins (genetics), Viral Fusion Proteins (metabolism).
- MESH :
- chemical , chemistry : Alanine, Phenylalanine, Spike Glycoprotein, Coronavirus, Tryptophan, Viral Fusion Proteins.
- chemical , genetics : Alanine, Phenylalanine, Spike Glycoprotein, Coronavirus, Viral Fusion Proteins.
- genetics : Protein Binding, Protein Interaction Domains and Motifs, Protein Multimerization, SARS Virus.
- metabolism : Cell Membrane, Peptide Fragments, SARS Virus, Spike Glycoprotein, Coronavirus, Viral Fusion Proteins.
- chemical , physiology : Tryptophan.
- virology : Cell Membrane.
- Amino Acid Substitution, Animals, Chlorocebus aethiops, Vero Cells.
Abstract
The spike (S) protein of severe acute respiratory syndrome-associated CoV (SARS-CoV) mediates membrane fusion and viral entry. These events involve structural rearrangements, including heteromerization between two heptad repeats (HR1 and HR2) to form a trimer of dimers as a six-helix bundle (6-HB), a quaternary protein structure that brings two distant clusters of hydrophobic sequences into the proximity of each other, the internal fusion peptide (IFP) preceding HR1, and the highly conserved tryptophan (Trp)-rich membrane proximal external region (MPER) following HR2. Here, we show that MPER can undergo self-oligomerization and heteromerization with IFP, events that are Trp-dependent. To delineate the roles of Trp residues of MPER in forming these quaternary structures and interacting with membranes, we employed a panel of synthetic peptides: MPER peptide (M-wt) and its alanine (Ala) and phenylalanine (Phe) analogues. Ala substitutions of Trp inhibited its association with cellular membranes. Chemical cross-linking experiments showed that M-wt can self-interact to form oligomers and cross-interact with IFP23, a synthetic IFP peptide, to form a heterohexamer. In comparison, little high-order oligomer was formed between M-wt and fusion peptide. The specific interaction between M-wt and IFP23 was confirmed by immunofluorescence staining experiments. In aqueous solutions, both M-wt and IFP23 displayed random secondary structures that became helical in hydrophobic solvents. Triple-Ala substitutions of Trp in M-wt, but not the corresponding triple-Phe analogue, disrupted oligomerization of M-wt and hetero-oligomerization of M-wt with IFP23. Overall, our results show that Trp residues of MPER play a key role in maintaining the structure and functions of MPER, allowing it to interact with IFP to form a MPER-IFP heteromer, a putative quaternary structure extending from the 6-HB, and function in membrane fusion. Finally, we showed that a MPER peptide could serve as an inhibitor in the entry process.
DOI: 10.1021/bi501352u
PubMed: 25668103
Affiliations:
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Le document en format XML
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Tam</name></author></analytic><series><title level="j">Biochemistry</title><idno type="eISSN">1520-4995</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Alanine (chemistry)</term><term>Alanine (genetics)</term><term>Amino Acid Substitution</term><term>Animals</term><term>Cell Membrane (metabolism)</term><term>Cell Membrane (virology)</term><term>Chlorocebus aethiops</term><term>Peptide Fragments (metabolism)</term><term>Phenylalanine (chemistry)</term><term>Phenylalanine (genetics)</term><term>Protein Binding (genetics)</term><term>Protein Interaction Domains and Motifs (genetics)</term><term>Protein Multimerization (genetics)</term><term>SARS Virus (genetics)</term><term>SARS Virus (metabolism)</term><term>Spike Glycoprotein, Coronavirus (chemistry)</term><term>Spike Glycoprotein, Coronavirus (genetics)</term><term>Spike Glycoprotein, Coronavirus (metabolism)</term><term>Tryptophan (chemistry)</term><term>Tryptophan (physiology)</term><term>Vero Cells</term><term>Viral Fusion Proteins (chemistry)</term><term>Viral Fusion Proteins (genetics)</term><term>Viral Fusion Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Alanine ()</term><term>Alanine (génétique)</term><term>Animaux</term><term>Cellules Vero</term><term>Fragments peptidiques (métabolisme)</term><term>Glycoprotéine de spicule des coronavirus ()</term><term>Glycoprotéine de spicule des coronavirus (génétique)</term><term>Glycoprotéine de spicule des coronavirus (métabolisme)</term><term>Liaison aux protéines (génétique)</term><term>Membrane cellulaire (métabolisme)</term><term>Membrane cellulaire (virologie)</term><term>Motifs et domaines d'intéraction protéique (génétique)</term><term>Multimérisation de protéines (génétique)</term><term>Phénylalanine ()</term><term>Phénylalanine (génétique)</term><term>Protéines de fusion virale ()</term><term>Protéines de fusion virale (génétique)</term><term>Protéines de fusion virale (métabolisme)</term><term>Substitution d'acide aminé</term><term>Tryptophane ()</term><term>Tryptophane (physiologie)</term><term>Virus du SRAS (génétique)</term><term>Virus du SRAS (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Alanine</term><term>Phenylalanine</term><term>Spike Glycoprotein, Coronavirus</term><term>Tryptophan</term><term>Viral Fusion Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Alanine</term><term>Phenylalanine</term><term>Spike Glycoprotein, Coronavirus</term><term>Viral Fusion Proteins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Protein Binding</term><term>Protein Interaction Domains and Motifs</term><term>Protein Multimerization</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Alanine</term><term>Glycoprotéine de spicule des coronavirus</term><term>Liaison aux protéines</term><term>Motifs et domaines d'intéraction protéique</term><term>Multimérisation de protéines</term><term>Phénylalanine</term><term>Protéines de fusion virale</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cell Membrane</term><term>Peptide Fragments</term><term>SARS Virus</term><term>Spike Glycoprotein, Coronavirus</term><term>Viral Fusion Proteins</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Fragments peptidiques</term><term>Glycoprotéine de spicule des coronavirus</term><term>Membrane cellulaire</term><term>Protéines de fusion virale</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Tryptophane</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Tryptophan</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Membrane cellulaire</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Cell Membrane</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Substitution</term><term>Animals</term><term>Chlorocebus aethiops</term><term>Vero Cells</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Alanine</term><term>Animaux</term><term>Cellules Vero</term><term>Glycoprotéine de spicule des coronavirus</term><term>Phénylalanine</term><term>Protéines de fusion virale</term><term>Substitution d'acide aminé</term><term>Tryptophane</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The spike (S) protein of severe acute respiratory syndrome-associated CoV (SARS-CoV) mediates membrane fusion and viral entry. These events involve structural rearrangements, including heteromerization between two heptad repeats (HR1 and HR2) to form a trimer of dimers as a six-helix bundle (6-HB), a quaternary protein structure that brings two distant clusters of hydrophobic sequences into the proximity of each other, the internal fusion peptide (IFP) preceding HR1, and the highly conserved tryptophan (Trp)-rich membrane proximal external region (MPER) following HR2. Here, we show that MPER can undergo self-oligomerization and heteromerization with IFP, events that are Trp-dependent. To delineate the roles of Trp residues of MPER in forming these quaternary structures and interacting with membranes, we employed a panel of synthetic peptides: MPER peptide (M-wt) and its alanine (Ala) and phenylalanine (Phe) analogues. Ala substitutions of Trp inhibited its association with cellular membranes. Chemical cross-linking experiments showed that M-wt can self-interact to form oligomers and cross-interact with IFP23, a synthetic IFP peptide, to form a heterohexamer. In comparison, little high-order oligomer was formed between M-wt and fusion peptide. The specific interaction between M-wt and IFP23 was confirmed by immunofluorescence staining experiments. In aqueous solutions, both M-wt and IFP23 displayed random secondary structures that became helical in hydrophobic solvents. Triple-Ala substitutions of Trp in M-wt, but not the corresponding triple-Phe analogue, disrupted oligomerization of M-wt and hetero-oligomerization of M-wt with IFP23. Overall, our results show that Trp residues of MPER play a key role in maintaining the structure and functions of MPER, allowing it to interact with IFP to form a MPER-IFP heteromer, a putative quaternary structure extending from the 6-HB, and function in membrane fusion. Finally, we showed that a MPER peptide could serve as an inhibitor in the entry process. </div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Liao, Ying" sort="Liao, Ying" uniqKey="Liao Y" first="Ying" last="Liao">Ying Liao</name><name sortKey="Neo, Tuan Ling" sort="Neo, Tuan Ling" uniqKey="Neo T" first="Tuan Ling" last="Neo">Tuan Ling Neo</name><name sortKey="Tam, James P" sort="Tam, James P" uniqKey="Tam J" first="James P" last="Tam">James P. Tam</name><name sortKey="Zhang, Si Min" sort="Zhang, Si Min" uniqKey="Zhang S" first="Si Min" last="Zhang">Si Min Zhang</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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