The aminoterminal insulin-like growth factor (IGF) binding domain of IGF binding protein-3 cannot be functionally substituted by the structurally homologous domain of CCN3.
IGF binding proteins (IGFBPs) are a family of structurally homologous proteins that bind IGFs with high affinities and can modulate IGF activity. The IGF binding site has been shown to comprise residues in both the aminoterminal and carboxyterminal domains. In recent years several proteins including members of the CCN (connective tissue growth factor, Cyr61, and nephroblastoma overexpressed) family were recognized as having structural homology in their aminoterminal domains to the IGFBPs. Despite their low or undetectable IGF binding ability, a proposal was made to rename them as IGFBP-related proteins. To test whether the aminoterminal domain of a CCN protein can fulfill the high-affinity IGF binding function of an IGFBP, we created a chimera in which the aminoterminal domain of IGFBP-3 was substituted with the aminoterminal domain of CCN3 (previously known as Nov). The CCN3-IGFBP-3 chimera bound IGFs and inhibited IGF activity very weakly, similar to CCN3 itself. Although structurally similar, the aminoterminal domain of CCN3 is unable to replace the aminoterminal domain of IGFBP-3 in forming a high-affinity IGF-binding site. These results argue against a direct role of CCN3 in the regulation of IGF bioavailability and indicate that the nomenclature of IGFBP-related proteins (which implies functional relationship to the classical IGFBPs) is inappropriate for CCN proteins.
Yan
Xiaolang
X
Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia.
Baxter
Robert C
RC
Perbal
Bernard
B
Firth
Sue M
SM
D000595:Amino Acid Sequence; D001665:Binding Sites; D055513:Connective Tissue Growth Factor; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000737:chemistry* / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D055514:Nephroblastoma Overexpressed Protein; D010766:Phosphorylation; D013002:Somatomedins / Q000378:metabolism*; D013329:Structure-Activity Relationship
C526317:CCN2 protein, human; C526319:CCN3 protein, human; D017874:Immediate-Early Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D036341:Intercellular Signaling Peptides and Proteins; D055514:Nephroblastoma Overexpressed Protein; D013002:Somatomedins; D055513:Connective Tissue Growth Factor