title: An exon splice enhancer primes IGF2:IGF2R binding site structure and function evolution.
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.
authors.affiliation: Department of Organic and Biological Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Williams
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Hoppe
authors.forename: Dellel
authors.initials: D
authors.lastname: Rezgui
authors.forename: Madeleine
authors.initials: M
authors.lastname: Strickland
authors.forename: Briony E
authors.initials: BE
authors.lastname: Forbes
authors.forename: Frank
authors.initials: F
authors.lastname: Grutzner
authors.forename: Susana
authors.initials: S
authors.lastname: Frago
authors.forename: Rosamund Z
authors.initials: RZ
authors.lastname: Ellis
authors.forename: Pakorn
authors.initials: P
authors.lastname: Wattana-Amorn
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Prince
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Zaccheo
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Nolan
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mungall
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Crump
authors.forename: A Bassim
authors.initials: AB
authors.lastname: Hassan
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D019143:Evolution, Molecular; D005091:Exons; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000737:chemistry* / Q000145:classification / Q000235:genetics; D008969:Molecular Sequence Data; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D017527:Receptor, IGF Type 2 / Q000737:chemistry* / Q000145:classification / Q000235:genetics; D013045:Species Specificity
chemical_list: D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II