TY - JOUR
T1 - Structural intermediates in influenza haemagglutinin-mediated fusion
AU - Chernomordik, Leonid V.
AU - Leikina, Eugenia
AU - Kozlov, Michael M.
AU - Frolov, Vadim A.
AU - Zimmerberg, Joshua
PY - 1999
Y1 - 1999
N2 - Fusion pore formation in the haemagglutinin (HA)-mediated fusion is a culmination of a multistep process, which involves low-pH triggered refolding of HA and rearrangement of membrane lipid bilayers. This rearrangement was arrested or slowed down by either altering lipid composition of the membranes, or lowering the density of HA, and/or temperature. The results suggest that fusion starts with the lateral assembly of activated HA into multimeric complexes surrounding future fusion sites. The next fusion stage involves hemifusion, i.e. merger of only contacting membrane monolayers. Lysophosphatidylcholine reversibly arrests fusion prior to this hemifusion stage. In the normal fusion pathway, hemifusion is transient and is not accompanied by any measurable transfer of lipid probes between the membranes. A temperature of 4°C stabilizes this 'restricted hemifusion' intermediate. The restriction of lipid flow through the restricted hemifusion site is HA-dependent and can be released by partial cleaving of low pH-forms of HA with mild proteinase K treatment. Lipid effects indicate that fusion proceeds through two different lipid-involving intermediates, which are characterized by two opposite curvatures of the lipid monolayer. Hemifusion involves formation of a stalk, a local bent connection between the outer membrane monolayers. Fusion pore formation apparently involves bending of the inner membrane monolayers, which come together in hemifusion. To couple low pH-induced refolding of HA with lipid rearrangements, it is proposed that the extension of the α-helical coiled coil of HA pulls fusion peptides inserted into the HA expressing membrane and locally bends the membrane into a saddle-like shape. Elastic energy drives self assembly of these HA containing membrane elements into a ring-like complex and causes the bulging of the host membrane into a dimple growing towards the target membrane. Bending stresses in the lipidic top of the dimple facilitate membrane fusion.
AB - Fusion pore formation in the haemagglutinin (HA)-mediated fusion is a culmination of a multistep process, which involves low-pH triggered refolding of HA and rearrangement of membrane lipid bilayers. This rearrangement was arrested or slowed down by either altering lipid composition of the membranes, or lowering the density of HA, and/or temperature. The results suggest that fusion starts with the lateral assembly of activated HA into multimeric complexes surrounding future fusion sites. The next fusion stage involves hemifusion, i.e. merger of only contacting membrane monolayers. Lysophosphatidylcholine reversibly arrests fusion prior to this hemifusion stage. In the normal fusion pathway, hemifusion is transient and is not accompanied by any measurable transfer of lipid probes between the membranes. A temperature of 4°C stabilizes this 'restricted hemifusion' intermediate. The restriction of lipid flow through the restricted hemifusion site is HA-dependent and can be released by partial cleaving of low pH-forms of HA with mild proteinase K treatment. Lipid effects indicate that fusion proceeds through two different lipid-involving intermediates, which are characterized by two opposite curvatures of the lipid monolayer. Hemifusion involves formation of a stalk, a local bent connection between the outer membrane monolayers. Fusion pore formation apparently involves bending of the inner membrane monolayers, which come together in hemifusion. To couple low pH-induced refolding of HA with lipid rearrangements, it is proposed that the extension of the α-helical coiled coil of HA pulls fusion peptides inserted into the HA expressing membrane and locally bends the membrane into a saddle-like shape. Elastic energy drives self assembly of these HA containing membrane elements into a ring-like complex and causes the bulging of the host membrane into a dimple growing towards the target membrane. Bending stresses in the lipidic top of the dimple facilitate membrane fusion.
KW - Bending stress
KW - Fusion
KW - Haemagglutinin
KW - Hemifusion
KW - Membrane dimple
UR - http://www.scopus.com/inward/record.url?scp=0032901325&partnerID=8YFLogxK
U2 - 10.1080/096876899294733
DO - 10.1080/096876899294733
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
AN - SCOPUS:0032901325
SN - 0968-7688
VL - 16
SP - 33
EP - 42
JO - Molecular Membrane Biology
JF - Molecular Membrane Biology
IS - 1
ER -
