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Science 338 (6111): 1209-1213

Copyright © 2012 by the American Association for the Advancement of Science

An Exon Splice Enhancer Primes IGF2:IGF2R Binding Site Structure and Function Evolution

Christopher Williams,1,* Hans-Jürgen Hoppe,2,* Dellel Rezgui,2 Madeleine Strickland,1 Briony E. Forbes,3 Frank Grutzner,3 Susana Frago,2 Rosamund Z. Ellis,1 Pakorn Wattana-Amorn,1 Stuart N. Prince,2 Oliver J. Zaccheo,2 Catherine M. Nolan,4 Andrew J. Mungall,5 E. Yvonne Jones,6 Matthew P. Crump,1,{dagger} A. Bassim Hassan2,{dagger}

Abstract: Placental development and genomic imprinting coevolved with parental conflict over resource distribution to mammalian offspring. The imprinted genes IGF2 and IGF2R code for the growth promoter insulin-like growth factor 2 (IGF2) and its inhibitor, mannose 6-phosphate (M6P)/IGF2 receptor (IGF2R), respectively. M6P/IGF2R of birds and fish do not recognize IGF2. In monotremes, which lack imprinting, IGF2 specifically bound M6P/IGF2R via a hydrophobic CD loop. We show that the DNA coding the CD loop in monotremes functions as an exon splice enhancer (ESE) and that structural evolution of binding site loops (AB, HI, FG) improved therian IGF2 affinity. We propose that ESE evolution led to the fortuitous acquisition of IGF2 binding by M6P/IGF2R that drew IGF2R into parental conflict; subsequent imprinting may then have accelerated affinity maturation.

1 Department of Organic and Biological Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
2 Cancer Research UK Tumour Growth Control Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
3 School of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, Australia.
4 School of Biology and Environmental Science, University College Dublin, Belfield, Dublin, Ireland.
5 Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada.
6 Cancer Research UK Receptor Structure Research Group, Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

* These authors contributed equally to this work.

{dagger} These authors contributed equally to this work. To whom correspondence should be addressed. E-mail: bass.hassan{at}path.ox.ac.uk (A.B.H.); matt.crump{at}bristol.ac.uk (M.P.C.)


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