Kinetics of insulin-like growth factor II (IGF-II) interaction with domain 11 of the human IGF-II/mannose 6-phosphate receptor: function of CD and AB loop solvent-exposed residues

Journal of Molecular Biology
Oliver J ZaccheoA Bassim Hassan

Abstract

Ligands of the IGF-II/mannose 6-phosphate receptor (IGF2R) include IGF-II and mannose 6-phosphate modified proteins. Disruption of the negative regulatory effects of IGF2R on IGF-II-induced growth can lead to embryonic lethality and cancer promotion. Of the 15 IGF2R extracellular domains, domains 1-3 and 11 are known to have a conserved beta-barrel structure similar to that of avidin and the cation-dependent mannose 6-phosphate receptor, yet only domain 11 binds IGF-II with high specificity and affinity. In order to define the functional basis of this critical biological interaction, we performed alanine mutagenesis of structurally determined solvent-exposed loop residues of the IGF-II-binding site of human domain 11, expressed these mutant forms in Pichia pastoris, and determined binding kinetics with human IGF-II using isothermal calorimetry and surface plasmon resonance with transition state thermodynamics. Two hydrophobic residues in the CD loop (F1567 and I1572) were essential for binding, with a further non-hydrophobic residue (T1570) that slows the dissociation rate. Aside from alanine mutations of AB loop residues that decrease affinity by modifying dissociation rates (e.g. Y1542), a novel mutation (E1544A) of the AB lo...Continue Reading

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Citations

Jun 8, 2012·EMBO Molecular Medicine·Victoria L HaleyA Bassim Hassan
Oct 3, 2009·Trends in Biochemical Sciences·James BrownBriony E Forbes
Aug 4, 2009·Cancer Letters·Irena Martin-Kleiner, Koraljka Gall Troselj
May 4, 2016·Proceedings of the National Academy of Sciences of the United States of America·Susana FragoAndrew Bassim Hassan
Nov 30, 2007·The EMBO Journal·James BrownE Yvonne Jones
Jan 18, 2008·Journal of Molecular Recognition : JMR·Oksana Okhrimenko, Ilian Jelesarov
Dec 13, 2007·Journal of Molecular Recognition : JMR·Rebecca L Rich, David G Myszka
Sep 3, 2020·PloS One·Pavlo PotalitsynLenka Žáková
May 4, 2007·The Journal of Biological Chemistry·Carlie DelaineBriony E Forbes
May 12, 2009·International Journal of Biological Macromolecules·Yadavalli SivaramakrishnaNadimpalli Siva Kumar

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