A novel binding site for the human insulin-like growth factor-II (IGF-II)/mannose 6-phosphate receptor on IGF-II.
The mammalian insulin-like growth factor (IGF)-II/cation-independent mannose 6-phosphate receptor (IGF2R) binds IGF-II with high affinity. By targeting IGF-II to lysosomal degradation, it plays a role in the maintenance of correct IGF-II levels in the circulation and in target tissues. Loss of IGF2R function is associated with tumor progression; therefore, the IGF2R is often referred to as a tumor suppressor. The interaction between IGF2R and IGF-II involves domains 11 and 13 of the 15 extracellular domains of the receptor. Recently, a hydrophobic binding region was identified on domain 11 of the IGF2R. In contrast, relatively little is known about the residues of IGF-II that are involved in IGF2R binding and the determinants of IGF2R specificity for IGF-II over the structurally related IGF-I. Using a series of novel IGF-II analogues and surface plasmon resonance assays, this study revealed a novel binding surface on IGF-II critical for IGF2R binding. The hydrophobic residues Phe(19) and Leu(53) are critical for IGF2R binding, as are residues Thr(16) and Asp(52). Furthermore, Thr(16) was identified as playing a major role in determining why IGF-II, but not IGF-I, binds with high affinity to the IGF2R.
Delaine
Carlie
C
School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
Alvino
Clair L
CL
McNeil
Kerrie A
KA
Mulhern
Terrance D
TD
Gauguin
Lisbeth
L
De Meyts
Pierre
P
Jones
E Yvonne
EY
Brown
James
J
Wallace
John C
JC
Forbes
Briony E
BE
D019943:Amino Acid Substitution; D001224:Aspartic Acid / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D002942:Circular Dichroism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007334:Insulin-Like Growth Factor I / Q000737:chemistry / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010649:Phenylalanine / Q000378:metabolism; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D017527:Receptor, IGF Type 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D013912:Threonine / Q000378:metabolism
D017527:Receptor, IGF Type 2; D013912:Threonine; D001224:Aspartic Acid; D010649:Phenylalanine; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D007930:Leucine