Polar Residues and Their Positional Context Dictate the Transmembrane Domain Interactions of Influenza A Neuraminidases

Stockholm University, Sweden.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2013; 288(15). DOI: 10.1074/jbc.M112.440230
Source: PubMed


Interactions that facilitate transmembrane domain (TMD) dimerization have been identified mainly using synthetic TMDs. Here,
we investigated how inherent properties within natural TMDs modulate their interaction strength by exploiting the sequence
variation in the nine neuraminidase subtypes (N1–N9) and the prior knowledge that a N1 TMD oligomerizes. Initially, consensus
TMDs were created from the influenza A virus database, and their interaction strengths were measured in a biological membrane
system. The TMD interactions increased with respect to decreasing hydrophobicity across the subtypes (N1–N9) and within the
human N1 subtype where the N1 TMDs from the pandemic H1N1 strain of swine origin were found to be significantly less hydrophobic.
The hydrophobicity correlation was attributed to the conserved amphipathicity within the TMDs as the interactions were abolished
by mutating residues on the polar faces that are unfavorably positioned in the membrane. Similarly, local changes enhanced
the interactions only when a larger polar residue existed on the appropriate face in an unfavorable membrane position. Together,
the analysis of this unique natural TMD data set demonstrates how polar-mediated TMD interactions from bitopic proteins depend
on which polar residues are involved and their positioning with respect to the helix and the membrane bilayer.

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