title: Delineation of the IGF-II C domain elements involved in binding and activation of the IR-A, IR-B and IGF-IR.
abstract: OBJECTIVE
  Human insulin-like growth factor-I and -II (IGF-I and -II) ligands share a high degree of sequence and structural homology. Despite their similarities, IGF-I and IGF-II exhibit differential receptor binding and activation characteristics. The C domains of IGF-I and IGF-II are the primary determinants of binding specificity to the insulin-like growth factor I receptor (IGF-IR), insulin receptor exon 11- (IR-A) and exon 11+ (IR-B) isoforms.
  
  
  METHODS
  Three IGF-II analogues were generated in order to delineate the C domain residues that confer the differential receptor binding affinity and activation properties of the IGFs. Chimeric IGF-II analogues IGF-IICI(N) and IGF-IICI(C) contained partial IGF-I C domain substitutions (IGF-I residues underlined) GYGSSSRRSR and SRVSRRAPQT, respectively.
  
  
  RESULTS
  The IGF-IICI(N) analogue bound the IR-A and IGF-IR with high affinity but bound the IR-B with a relatively lower affinity than IGF-II, suggesting a negative interaction between the exon-11 encoded peptide in the IR-B and the C-domain. The ability of IGF-IICI(N) to activate receptors and elicit cell viability responses was generally proportional to its relative receptor binding affinity but appeared to act as a partial agonist equivalent to IGF-I when binding and activating the IGF-IR. In contrast, IGF-IICI(C) bound IGF-IR with high affinity but elicited lower receptor activation and cell viability responses. Analogue IGF-IICI(S) contained a truncated IGF-I C domain (GSSSRRAT) and generally displayed a relatively poor ability to bind, activate and elicit viability responses via each receptor.
  
  
  CONCLUSIONS
  Together, the IGF analogues demonstrate that both flanks of the IGF-II C domain play important roles in the greater ability of IGF-II to bind and activate IR receptors than IGF-I.
authors.affiliation: Commonwealth Scientific Industrial Research Organisation, Preventative Health National Research Flagship, Adelaide, South Australia 5000, Australia; School of Biological Sciences, Flinders University, Adelaide, South Australia 5001, Australia.
authors.forename: S T
authors.initials: ST
authors.lastname: Henderson
authors.affiliation: Commonwealth Scientific Industrial Research Organisation, Preventative Health National Research Flagship, Adelaide, South Australia 5000, Australia.
authors.forename: G V
authors.initials: GV
authors.lastname: Brierley
authors.affiliation: Commonwealth Scientific Industrial Research Organisation, Preventative Health National Research Flagship, Adelaide, South Australia 5000, Australia.
authors.forename: K H
authors.initials: KH
authors.lastname: Surinya
authors.affiliation: Commonwealth Scientific Industrial Research Organisation, Preventative Health National Research Flagship, Adelaide, South Australia 5000, Australia.
authors.forename: I K
authors.initials: IK
authors.lastname: Priebe
authors.affiliation: School of Biological Sciences, Flinders University, Adelaide, South Australia 5001, Australia.
authors.forename: D E A
authors.initials: DE
authors.lastname: Catcheside
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: J C
authors.initials: JC
authors.lastname: Wallace
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: B E
authors.initials: BE
authors.lastname: Forbes
authors.affiliation: Commonwealth Scientific Industrial Research Organisation, Preventative Health National Research Flagship, Adelaide, South Australia 5000, Australia. Electronic address: leah.cosgrove@csiro.au.
authors.forename: L J
authors.initials: LJ
authors.lastname: Cosgrove
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D041702:BALB 3T3 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C583557:IGF1 protein, human; C000597236:IGF1R protein, human; C035170:IGF2 protein, human; D020033:Protein Isoforms; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
keywords: Binding; Chimera; IGF-I; IGF-II; Insulin receptor; Structure