Serpins: a1-antitrypsin

Family ties

a1-Antitrypsin is one of over 500 known serpins that have been identified in a variety of species from bacteria, archaea, eukaryotes and eukaryotic viruses. The human genome alone encodes for at least 35 different members that can be placed into nine evolutionarily distinct clades, A-I. Most serpins are secreted and circulate in plasma, where they affect such divergent processes as blood coagulation, complement activation, fibrinolysis, angiogenesis, kinninogen activation, inflammation, tumour suppression, cell death pathways, phagocytosis and dorsal-ventral patterning. Other serpins lack signal peptides and are confined within cells (intracellular ov-serpins named after one of their members, ovalbumin), where they act to protect the cell from protease-induced damage. Not all serpins act as protease inhibitors, some having roles such as chaperones, hormone transport proteins, and blood pressure regulators.

Most of the variation between serpins occurs in the reactive centre loop (RCL), which is crucial for target recognition and for conformational changes upon target binding. The RCL can adopt a range of conformations in different serpins, which help determine the specificity of the serpin. Consequently, the RCL is the fastest evolving region within the serpin nucleotide sequence, this hypervariability driving the functional diversification of serpins. This is evident with a1-antitrypsin, where in humans it is encoded by a single gene, whereas in mice it is represented by a cluster of six genes, the variation between them occurring within the region encoding the RCL domain.

P01009 Human a1-antitrypsin entry from InterPro

InterPro entry	Method accession	Graphical match	Method name
IPR000215	PF00079		Serpin
IPR000215	PS00284		SERPIN
IPR000215	SM00093		SERPIN
IPR000215	SSF56574		Serpin
Classification	PDB chain/Domain ID	PDB chain/Structural Domains
1qlp	1qlpa		PDB
2.30.39.10.4	1qlpA1		CATH
3.30.497.10.1	1qlpA2		CATH
e.1.1.1	d1qlpa_		SCOP

What InterPro tells us

From the graphical match above, you can see that the signatures in InterPro for human a1-antitrypsin are found in one entry, IPR000215. IPR000215 represents the family of proteinase I4 inhibitors, serpins, which includes almost 700 members. It is represented by four signatures: PF00079 from the PFAM database, PS00284 from the PROSITE database, SSF56574 from the SUPERFAMILY database, and SM00093 from the SMART database, the latter being centred on a well-conserved Pro-Phe sequence near the C-terminal side of the reactive bond. The N-terminal end of these signatures varies, in part because the PFAM and SMART signatures are based on sequence conservation, while the SUPERFAMILY signature is based on structural considerations.

The remaining four entries in the table above are from the structural database PDB, and from the structural classification databases CATH and SCOP (the names such as 1qlpA1 are derived from the PDB entry upon which they are based; here PDB entry 1qlp, chain a, region 1). The graphical match for the PDB entry, 1qlpa, displays the length of the original PDB structure. Both the SCOP and the CATH databases describe the structural features and classification of protein structure. The SCOP entry, d1qlpa_, covers the entire protein, while the two CATH entries, 1qlpA1 and 1qlpA2, divide the protein into two domains based on topological differences between the two regions of the protein.

What the structure tells us

A description and visualisation of the structural features of a1-antitrypsin can be found at the PDB database. The crystallographic structures of a1-antitrypsin have provided insight into the general mode of action of serpins. These structures have shown the native active conformation to be a kinetically trapped folding intermediate, thus providing information on the mechanisms involved in protein folding.

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