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α₁-Antitrypsin (A1AT) is a 45 kDa serine proteinase inhibitor (serpin) that is present at high concentrations in serum and is essential for the inhibition of neutrophil elastase activity. A1AT is unusual among proteins in that the native fold is not the most stable state, but rather is a metastable form that undergoes a large scale conformational remodelling upon interaction with the substrate protease. However, similar conformational rearrangements in the absence of substrate may lead to polymerisation of the protein and hence to loss of function or accumulation in the liver.

This presents a fascinating challenge to the regulation of dynamics within the protein: to have sufficient conformational flexibility to maintain inhibitory activity, while minimising the risk of misfolding from the metastable native state. We have therefore initiated a study of the conformational landscape of A1AT using NMR spectroscopy. We have completed the full assignment of this 45 kDa protein, and have identified a new pathogenic variant, K154N, for which we have also reported a preliminary characterisation using NMR spectroscopy.

Further reading:

• Structural dynamics associated with intermediate formation in an archetypal conformational disease. Nyon MP, Lévy GR, Segu L, Cabrita LD, Kirkpatrick J, Benoit D, Roussel BD, Patschull AOM, Barrett TE, Ekeowa UI, Kerr R, Waudby CA, Kalsheker N, Hill M, Thalassinos K, Lomas DA, Christodoulou J, Gooptu B. Structure (2012) 20, 504-512. pubmed | pdf
• ¹H, ¹⁵N and ¹³C backbone resonance assignments of the archetypal serpin α₁-antitrypsin. Nyon MP, Kirkpatrick J, Cabrita LD, Christodoulou J, Gooptu B. Biomol NMR Assign (2011) 6, 153-6. pubmed | pdf