tetano
Editor, Senior Moderator
Order and disorder control the functional rearrangement of influenza hemagglutinin
Xingcheng Lina,1,
Nathanial R. Eddya,1,
Jeffrey K. Noela,
Paul C. Whitfordb,
Qinghua Wangc,
Jianpeng Maa,c,d, and
José N. Onuchica,2
Author Affiliations
Contributed by José N. Onuchic, July 7, 2014 (sent for review May 21, 2014)
Significance
Influenza hemagglutinin (HA), a viral surface glycoprotein, undergoes a critical and large conformational rearrangement to promote fusion of the viral membrane with the host membrane. Unlike the variable receptor binding domain HA1, the coiled-coil domain HA2 is highly conserved, making HA2 a promising target for therapeutics. Furthermore, the structural similarity between influenza HA2 and other viral fusion proteins, including that of HIV, makes HA2 a valuable model system. We build a model using information from only the prefusion and postfusion configurations of HA2 and use molecular dynamics simulations to characterize the structural ensembles found during the conformational transition. We find that local unfolding facilitates interaction of HA2 with the host membrane and enables a quasi-stable asymmetric intermediate during the transition.
Abstract
Influenza hemagglutinin (HA), a homotrimeric glycoprotein crucial for membrane fusion, undergoes a large-scale structural rearrangement during viral invasion. X-ray crystallography has shown that the pre- and postfusion configurations of HA2, the membrane-fusion subunit of HA, have disparate secondary, tertiary, and quaternary structures, where some regions are displaced by more than 100 Å. To explore structural dynamics during the conformational transition, we studied simulations of a minimally frustrated model based on energy landscape theory. The model combines structural information from both the pre- and postfusion crystallographic configurations of HA2. Rather than a downhill drive toward formation of the central coiled-coil, we discovered an order-disorder transition early in the conformational change as the mechanism for the release of the fusion peptides from their burial sites in the prefusion crystal structure. This disorder quickly leads to a metastable intermediate with a broken threefold symmetry. Finally, kinetic competition between the formation of the extended coiled-coil and C-terminal melting results in two routes from this intermediate to the postfusion structure. Our study reiterates the roles that cracking and disorder can play in functional molecular motions, in contrast to the downhill mechanical interpretations of the “spring-loaded” model proposed for the HA2 conformational transition.
http://www.pnas.org/content/early/2014/07/31/1412849111
Xingcheng Lina,1,
Nathanial R. Eddya,1,
Jeffrey K. Noela,
Paul C. Whitfordb,
Qinghua Wangc,
Jianpeng Maa,c,d, and
José N. Onuchica,2
Author Affiliations
Contributed by José N. Onuchic, July 7, 2014 (sent for review May 21, 2014)
Significance
Influenza hemagglutinin (HA), a viral surface glycoprotein, undergoes a critical and large conformational rearrangement to promote fusion of the viral membrane with the host membrane. Unlike the variable receptor binding domain HA1, the coiled-coil domain HA2 is highly conserved, making HA2 a promising target for therapeutics. Furthermore, the structural similarity between influenza HA2 and other viral fusion proteins, including that of HIV, makes HA2 a valuable model system. We build a model using information from only the prefusion and postfusion configurations of HA2 and use molecular dynamics simulations to characterize the structural ensembles found during the conformational transition. We find that local unfolding facilitates interaction of HA2 with the host membrane and enables a quasi-stable asymmetric intermediate during the transition.
Abstract
Influenza hemagglutinin (HA), a homotrimeric glycoprotein crucial for membrane fusion, undergoes a large-scale structural rearrangement during viral invasion. X-ray crystallography has shown that the pre- and postfusion configurations of HA2, the membrane-fusion subunit of HA, have disparate secondary, tertiary, and quaternary structures, where some regions are displaced by more than 100 Å. To explore structural dynamics during the conformational transition, we studied simulations of a minimally frustrated model based on energy landscape theory. The model combines structural information from both the pre- and postfusion crystallographic configurations of HA2. Rather than a downhill drive toward formation of the central coiled-coil, we discovered an order-disorder transition early in the conformational change as the mechanism for the release of the fusion peptides from their burial sites in the prefusion crystal structure. This disorder quickly leads to a metastable intermediate with a broken threefold symmetry. Finally, kinetic competition between the formation of the extended coiled-coil and C-terminal melting results in two routes from this intermediate to the postfusion structure. Our study reiterates the roles that cracking and disorder can play in functional molecular motions, in contrast to the downhill mechanical interpretations of the “spring-loaded” model proposed for the HA2 conformational transition.
http://www.pnas.org/content/early/2014/07/31/1412849111