ECE2014 Poster Presentations Developmental Endocrinology (6 abstracts)
Crystal structure of Drosophila imaginal morphogenesis protein-Late 2 (IMP-L2) in free form and bound to Drosophila insulin-like peptide 5 (DILP5) and human Insulin-like growth factor-I (hIGF1).
Nikolaj Kulahin 1 , Christopher J. Watson 2 , Waseem Sajid 1 , Gerd Schluckebier 1 , Claus Kristensen 1 , Asser Sloth Andersen 1 , Ole Kristensen 3 , Matthias Norrman 1 , Pierre De Meyts 1 & Andrzej Marek Brzozowski 2
1Novo Nordisk A/S, Maaloev, Denmark; 2University of York, York, UK; 3University of Copenhagen, Copenhagen, Denmark.
The insulin signalling system including the insulin receptor tyrosine kinase (IRTK) is evolutionarily ancient. The Drosophila Melanogaster genome contains seven genes for insulin-like peptides (ILPs) that are expressed in neurosecretory cells in a highly tissue- and stage-specific pattern, DILP1–7. There is however only one IRTK (dIR). This system is important in the regulation of metabolism, growth, reproduction and lifespan. We reported in 2011 the crystal structure of Drosophila insulin-like peptide 5 (DILP5) (expressed in Saccharomyces Cerevisiae) at 1.85 A resolution, as well as its biological and receptor binding properties. DILP5 shares the canonical fold of the insulin peptide family and form dimers that differ from the mammalian and hagfish insulin dimers.
Drosophila Melanogaster also has a circulating ILP binding protein, called imaginal morphogenesis protein-Late 2 (IMP-L2), with no equivalent in mammals. It was cloned, expressed and purified in 2000 and was shown to bind human insulin and insulin-like growth factors. We showed in 2011 that it also binds DILP5. We now report the solution of the crystal structure of IMP-L2 in the free form as well as bound to DILP5 and to human insulin-like growth factor-I (hIGF1). Recombinant IMP-L2 was expressed in a Baculovirus expression system, purified and crystallized with selenium as heavy atom. IMP-L2 shows a bilobed structure with two IgG beta sheet modules folded together into a ‘baseball glove’. The structure is very different from the known partial structures of IGFBPs and dispels the concept that IMPL-2 is an orthologue of a human IGFBP. The complex of IMP-L2 with DILP5 shows a multimeric structure with two DILP5 molecules bound into the grooves between the beta sheets of two distinct IMP-L2s in a symmetrical tetrameric IMPL-2. In contrast, the IMPL-2 complex with hIGF-I is monomeric and reveals a novel conformation of IGF1 not seen in previous structures of IGF1.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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