Bird Flu - Haemagglutinin

The Haemagglutinin Molecule

Haemagglutinin is synthesized as a single polypeptide (HA₀), which assembles on the virus envelope as a trimer containing three structurally distinct regions: a globular head consisting of anti-parallel beta-sheets that form a beta-sandwich with a jelly-roll fold; a triple-stranded, coiled-coil, alpha-helical stalk; and a globular foot comprised of anti-parallel beta-sheets. The globular head, which is hydrophilic and contains a carbohydrate moiety, resides on the external surface of the membrane and contains the receptor-binding domain and an alpha-stalk domain with the HA₁/HA₂ cleavage site. The head region contains the variable antigenic determinants that account for differences in infectivity between strains. Attached to the head is a small, uncharged hydrophobic region that spans the membrane, linking the head to a smaller globular, hydrophilic domain residing on the inside of the membrane. Each monomer in the trimeric structure comprises of two disulphide-linked chains, HA₁ and HA₂. The N-terminus of HA₁ provides the central strand in the 5-stranded globular foot, while the rest of the HA₁ chain makes its way to the 8-stranded globular headpiece. HA₂ provides two alpha helices, which form part of the fibrous structure, a triple-stranded coiled-coil that stabilises the trimer, its C-terminus providing the remaining strands of the 5-stranded globular foot.

What InterPro Tells Us

P03437 Influenza A virus (strain A/Aichi/2/68 H3N2) haemagglutinin precursor

InterPro Domain Architecture

InterPro Entry	Signatures	Graphical Match	Method Name
IPR000149	PR00330		HEMAGGLUTN1
IPR001364	PD000225		Hemagglutn
IPR001364	PF00509		Hemagglutinin
IPR001364	PR00329		HEMAGGLUTN12
IPR008980	SSF49818		Capsid_hemag
Structural Features
1ha0	1ha0A
1qu1	1qu1A
2viu	2viuA
2viu	2viuB
2.10.77.10.1	2viuA2
3.90.209.20.2	2viuA1
3.90.20.10.1	1qu1F0
b.19.1.2	d2viua_
h.3.1.1	d1qu1a_

From the graphical match above, you can see that the signatures are grouped into three InterPro entries for influenza A virus haemagglutinin. These entries give information about the domain architecture of the protein, as well as its family relationships.

To look at the family relationships, we need to consider entry IPR001364, which represents the family of haemagglutinin proteins, and which has three signatures: PF00509 from the PFAM database, PR00329 from the PRINTS database, and PD000225 from the PRODOM database. These signatures cover the entire HA₀ molecule, which comprises HA₁ and HA₂.

The domain architecture of haemagglutinin consists of two chains: HA₁ and HA₂ (note, the division of the haemagglutinin trimer into the head, stalk and foot domains occurs at the 3-dimentional level). The N-terminal HA₁ chain is represented above by IPR000149, which has one signature: PR00330 from the PRINTS database. This entry is a child of the larger entry, IPR008980, which represents viral capsids and haemagglutinin HA1 chain, and which has one signature: SSF49818 from SUPERFAMILY. The HA₁ haemagglutinin chain is related in its beta-sandwich structure to the haemagglutinin domain of haemagglutinin-esterase fusion glycoprotein HEF1, and to the top domain of the virus capsid protein found in Bluetongue virus, Rice dwarf virus, African horse sickness virus, and Bovine virus - all these proteins form a superfamily and are represented in IPR008980.

The other chain, HA₂, is found at the C-terminal end of the HA₀ protein, and is represented by the InterPro entry IPR000386, however its signature, PR00331, does not hit this particular protein.

The remaining nine entries in the table above give information on the structure of this protein, presenting known structural data from the structural database PDB (green stripe) and the structural classification databases CATH (pink stripe) and SCOP (black stripe) (the names such as 2viuA1 are derived from the PDB entry upon which they are based, here PDB entry 2viu, chain A, fragment 1). The graphical match for the PDB entry 1ha0 displays the full length of the original PDB entry, here covering almost the entire protein. The CATH and SCOP entries breakdown the PDB data into its constituent domains and provide a structural classification for each domain. This classification differs between SCOP and CATH. SCOP recognises two domains, HA₁ (d2viua_; beta-sandwich fold) and HA₂ (d1qu1a_; trimeric coiled-coil), while CATH recognises three domains, two for HA₁ (2viuA1, a/b, and 2viuA2, mainly b), and one for HA₂ (1qu1F0; a/b).

What the Structure Tells Us

Structures associated with influenza A virus haemagglutinin can be viewed using AstexViewer®, which is linked from the Match Table via the logo on the InterPro page (please note, there is no link directly from this page to the AstexViewer®, therefore you need to go to the link on the InterPro page for P03437). The AstexViewer® displays the PDB structure with the specific CATH or SCOP domain highlighted.

There are structures available for haemagglutinin from different strains of influenza viruses in the Protein Data Bank (PDB). A detailed description and visualisation of the structural features of haemagglutinin can be found at the PDB ‘Molecule of the Month’. The crystallographic structures of haemagglutinin proteins have provided insight into the mechanism of action of these important fusion surface proteins.

Next: Table of Haemagglutinin and Neuraminidase Proteins

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