The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin.


Abstract

Influenza is notable for its evolutionary capacity to escape immunity targeting the viral hemagglutinin. We used deep mutational scanning to examine the extent to which a high inherent mutational tolerance contributes to this antigenic evolvability. We created mutant viruses that incorporate most of the ≈10(4) amino-acid mutations to hemagglutinin from A/WSN/1933 (H1N1) influenza. After passaging these viruses in tissue culture to select for functional variants, we used deep sequencing to quantify mutation frequencies before and after selection. These data enable us to infer the preference for each amino acid at each site in hemagglutinin. These inferences are consistent with existing knowledge about the protein's structure and function, and can be used to create a model that describes hemagglutinin's evolution far better than existing phylogenetic models. We show that hemagglutinin has a high inherent tolerance for mutations at antigenic sites, suggesting that this is one factor contributing to influenza's antigenic evolution.

Submission Details

ID: yu9hJKJ93

Submitter: Shu-Ching Ou

Submission Date: Jan. 29, 2019, 11:11 a.m.

Version: 1

Publication Details
Thyagarajan B;Bloom JD,Elife (2014) The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin. PMID:25006036
Additional Information

Actual starting sequence: MKAKLLVLLYAFVATDADTICIGYHANNSTDTVDTILEKNVAVTHSVNLLEDSHNGKLCKLKGIAPLQLGKCNITGWLLGNPECDSLLPARSWSYIVETPNSENGACYPGDLIDYEELREQLSSVSSLERFEIFPKESSWPNHTFNGVTVSCSHRGKSSFYRNLLWLTKKGDSYPKLTNSYVNNKGKEVLVLWGVHHPSSSDEQQSLYSNGNAYVSVASSNYNRRFTPEIAARPKVRDQHGRMNYYWTLLEPGDTIIFEATGNLIAPWYAFALSRGFESGIITSNASMHECNTKCQTPQGAINSNLPFQNIHPVTIGECPKYVRSTKLRMVTGLRNIPSIQYRGLFGAIAGFIEGGWTGMIDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAVGKEFNNLEKRMENLNKKVDDGFLDIWTYNAELLVLLENERTLDFHDLNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCDNECMESVRNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI

Study Summary

Number of data points 11280
Proteins Hemagglutinin
Unique complexes 10717
Assays/Quantities/Protocols Experimental Assay: Amino acid preference
Libraries Variants for HA

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
5VLI 2017-09-27 1.8 Computationally designed inhibitor peptide HB1.6928.2.3 in complex with influenza hemagglutinin (A/PuertoRico/8/1934)
6ONA 2019-05-01 1.95 Crystal structure of Influenza hemagglutinin from strain A/Hickox/JY2/1940
1RVX 2004-03-30 2.2 1934 H1 Hemagglutinin in complex with LSTA
1RVZ 2004-03-30 2.25 1934 H1 Hemagglutinin in complex with LSTC
5W5S 2017-10-04 2.28 Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with cyclic peptide CP141019 (P5)
1RU7 2004-03-30 2.3 1934 Human H1 Hemagglutinin
5W5U 2017-10-04 2.46 Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with cyclic peptide CP141037 (P4)
5W6T 2017-10-04 2.59 Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with cyclic peptide CP151070 (P7)
1RUY 2004-03-30 2.7 1930 Swine H1 Hemagglutinin
5W6R 2017-10-04 2.73 Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with cyclic peptide CP141099 (P6)
5W6U 2017-10-04 2.88 Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with cyclic peptide CP121068 (P2)
5W6I 2017-10-04 3.1 Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with cyclic peptide CP141046 (P3)

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
90.3 Hemagglutinin A4K143 HEMA_I54A2
90.1 Hemagglutinin A4GCH5 HEMA_I83A1
90.3 Hemagglutinin P18875 HEMA_I79A4
90.3 Hemagglutinin A4GCJ7 HEMA_I80AA
90.5 Hemagglutinin A4GBX7 HEMA_I77AA
90.6 Hemagglutinin P18876 HEMA_I54A0
90.8 Hemagglutinin A4U7A6 HEMA_I51A0
90.8 Hemagglutinin P03453 HEMA_I77AB
91.2 Hemagglutinin P03454 HEMA_I33A0
91.3 Hemagglutinin Q0HD60 HEMA_I40A0
93.3 Hemagglutinin A4U6V2 HEMA_I45A0
93.3 Hemagglutinin A4GCK8 HEMA_I43A0
95.8 Hemagglutinin A4GCL9 HEMA_I35A3
96.3 Hemagglutinin A4GCI6 HEMA_I36A0
100.0 Hemagglutinin P03452 HEMA_I34A1