An NMR spectroscopic menage a trois - three tales about protein structure, folding, dynamics and metabolic context

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• Dr Horst Joachim Schirra
• Wednesday 20 September 2006, 11:30-12:30
• Chemistry U202.

If you have a question about this talk, please contact Sarah Meehan.

The structure of a protein is inextricably linked to its function, folding behaviour, and internal dynamics. In addition, the function of a protein is embedded in the metabolic context of a cell or a whole organism. We have been using a combination of NMR spectroscopy and molecular biology to study these relationships in three different cases: Proteinase inhibitors (PIs), cyclotides, and the growth hormone receptor. Nicotiana alata produces a series of 6 kDa trypsin and chymotrypsin inhibitors of the potato type II (PotII) PI family that are derived from the 43 kDa precursor protein ProPI, containing six amino acid repeats corresponding to six PI domains. ProPI is highly unusual in that the proteolytic processing occurs in the middle of these sequence repeats, meaning that the individual PI domains fold across the sequence repeat. This folding behaviour of intramolecular domain-swapping is unique to the PotII PIs. Studies in our group have been focussing on the structural basis for the folding behaviour of N. alata PI domains. The cyclotides are a family of disulfide-rich macrocyclic peptides with unique properties. They contain about 30 amino acids in a continuous cyclic peptide backbone. Here, we present the first systematic study of the backbone dynamics of kalata B1, the archetypal cyclotide. The molecule forms homotetramers at higher protein concentrations that might be functionally important. Our results show that the relaxation of kalata B1 is crucially influenced by the monomer-tetramer equilibrium. Thus, the data yield information not only on the internal dynamics of kalata B1, but also about its oligomerisation behaviour and the nature of its tetrameric state. Growth hormone is the key factor regulating postnatal growth and an important regulator of metabolism. We have used growth hormone receptor transgenic mice in a NMR metabonomic study of mouse urine to investigate how these mutations alter the metabolism of the mice. Our results point to a dramatically altered metabolism geared towards the development of adiposity. These results demonstrate the intricate interplay between structure, folding, dynamics, function and metabolic context in three fascinating families of biologically important proteins.

This talk is part of the Dobson Group - General Interest series.

This talk is included in these lists:

• Chemistry U202
• Dobson Group - General Interest

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