protein conformation
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The conformation of proteins is maintained by the tight packing of their amino-acid side-chains; even small changes that result from the replacement of a single amino acid can be sufficient to allow conformational unfolding.
This is especially true of some key domains of functional proteins, and is well illustrated by the serpins.
Serpins
The serpins, or serine proteinase inhibitors, are a superfamily of proteins that are found in a wide range of species, including plants, viruses and humans.
The family includes members as diverse as the plasma proteins alpha1-antitrypsin, alpha1-antichymotrypsin, C1 inhibitor, antithrombin III (AT3) and plasminogen activator inhibitor 1, which have key regulatory functions in the inflammatory, complement, coagulation and fibrinolytic cascades.
Serpins also include proteins that are involved in chromatin packing (the myeloid and erythroid nuclear termination state-specific protein or MENT), the neuron-specific protein neuroserpin and the egg-white protein ovalbumin.
Members of the serpin superfamily are characterized by greater than 30% amino-acid sequence homology with 1-antitrypsin and have a conserved tertiary structure.
Insights into the structure of the serpins have been crucial for understanding the molecular basis of the pathologies that are caused by mutations in these proteins.
The structure of the serpins is based on three beta-sheets (A–C) and an exposed mobile reactive loop that presents a peptide sequence as a pseudosubstrate for the target proteinase.
After docking with the proteinase, the serpin undergoes a striking conformational transition that swings the proteinase from the upper to the lower pole of the serpin, in association with the insertion of an extra strand into beta-sheet A.
This transition grossly distorts the overall structure of the proteinase, thereby causing its irreversible inhibition. The serpin bound to its target enzyme is then recognized by hepatic receptors as it passes through the liver and is cleared from the circulation.
Members of the serpin, or serine proteinase inhibitor, superfamily, such as alpha1-antitrypsin (A1AT), undergo a striking conformational transition to inhibit their target proteinase.
After docking, the target proteinase is inactivated by movement from the upper to the lower pole of the protein. This is associated with the insertion of the reactive loop of the serpin as an extra strand into beta-sheet A.
The inhibitory mechanism might be triggered spontaneously by certain point mutations, which result in diseases known as the serpinopathies.
The best characterized of these mutations is the Z variant of alpha1-antitrypsin (a E342K substitution at P17 (17 residues proximal to the P1 residue at the reactive centre) at the proximal hinge of the molecule (between beta-sheet A and the loop containing the reactive centre) or mutations in the shutter domain that open beta-sheet A to favour partial loop insertion and the formation of an unstable intermediate (M*).
The open beta-sheet A can either accept the loop of another molecule to form a dimer, which then extends into polymers, or its own loop to form a latent conformation.
Conformational instability of the serpins can also result from mutations in the distal hinge region.
References
Shorter J, Lindquist S. Prions as adaptive conduits of memory and inheritance. Nat Rev Genet. 2005 Jun;6(6):435-50. PMID: #15931169#