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SUMMARY:An NMR spectroscopic menage a trois - three tales about protein st
 ructure\, folding\, dynamics and metabolic context - Dr Horst Joachim Schi
 rra
DTSTART:20060920T103000Z
DTEND:20060920T113000Z
UID:TALK5309@talks.cam.ac.uk
CONTACT:Sarah Meehan
DESCRIPTION:The structure of a protein is inextricably linked to its\nfunc
 tion\, folding behaviour\, and internal dynamics. In addition\, the\nfunct
 ion of a protein is embedded in the metabolic context of a cell or a\nwhol
 e organism. We have been using a combination of NMR spectroscopy and\nmole
 cular biology to study these relationships in three different cases:\nProt
 einase inhibitors (PIs)\, cyclotides\, and the growth hormone receptor.\nN
 icotiana alata produces a series of 6 kDa trypsin and chymotrypsin\ninhibi
 tors of the potato type II (PotII) PI family that are derived from\nthe 43
  kDa precursor protein ProPI\, containing six amino acid repeats\ncorrespo
 nding to six PI domains. ProPI is highly unusual in that the\nproteolytic 
 processing occurs in the middle of these sequence repeats\,\nmeaning that 
 the individual PI domains fold across the sequence repeat.\nThis folding b
 ehaviour of intramolecular domain-swapping is unique to the\nPotII PIs. St
 udies in our group have been focussing on the structural basis\nfor the fo
 lding behaviour of N. alata PI domains. The cyclotides are a\nfamily of di
 sulfide-rich macrocyclic peptides with unique properties. They\ncontain ab
 out 30 amino acids in a continuous cyclic peptide backbone. Here\,\nwe pre
 sent the first systematic study of the backbone dynamics of kalata\nB1\, t
 he archetypal cyclotide. The molecule forms homotetramers at higher\nprote
 in concentrations that might be functionally important. Our results\nshow 
 that the relaxation of kalata B1 is crucially influenced by the\nmonomer-t
 etramer equilibrium. Thus\, the data yield information not only on\nthe in
 ternal dynamics of kalata B1\, but also about its oligomerisation\nbehavio
 ur and the nature of its tetrameric state. Growth hormone is the key\nfact
 or regulating postnatal growth and an important regulator of\nmetabolism. 
 We have used growth hormone receptor transgenic mice in a NMR\nmetabonomic
  study of mouse urine to investigate how these mutations alter\nthe metabo
 lism of the mice. Our results point to a dramatically altered\nmetabolism 
 geared towards the development of adiposity. These results\ndemonstrate th
 e intricate interplay between structure\, folding\, dynamics\,\nfunction a
 nd metabolic context in three fascinating families of\nbiologically import
 ant proteins.\n\n
LOCATION:Chemistry U202
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