How IGF-II Binds to the Human Type 1 Insulin-like Growth Factor Receptor

Abstract

Summary Human type 1 insulin-like growth factor receptor (IGF-1R) signals chiefly in response to the binding of insulin-like growth factor I. Relatively little is known about the role of insulin-like growth factor II signaling via IGF-1R, despite the affinity of insulin-like growth factor II for IGF-1R being within an order of magnitude of that of insulin-like growth factor I. Here, we describe the cryoelectron microscopy structure of insulin-like growth factor II bound to a leucine-zipper-stabilized IGF-1R ectodomain, determined in two conformations to a maximum average resolution of 3.2 Å. The two conformations differ in the relative separation of their respective points of membrane entry, and comparison with the structure of insulin-like growth factor I bound to IGF-1R reveals long-suspected differences in the way in which the critical C domain of the respective growth factors interact with IGF-1R.

Understanding IGF-II Action through Insights into Receptor Binding and Activation

“…The αCT shifts to accommodate the ligand, which makes contact via its site 1 residues [ 60 , 61 ]. As defined by Weis et al [ 62 ], site 1 contacts made between the ligand and the receptor L1 and αCT domains [ 62 , 63 , 64 ]. In the case of IGF-II and IGF-I binding IGF-1R as well as insulin binding IR, the residues identified in site-directed mutagenesis studies correspond to those involved in this site 1 interaction ( Table 1 ).…”

“…Recently, a structure of the IGF-II:IGF-1R complex was determined using cryoEM to an average maximum resolution of 3.2 Å ( Figure 4 b) [ 63 ]. The site 1 ligand binding interaction is similar to the previous insulin:IR and IGF-I:IGF-1R structures [ 64 , 69 , 70 ].…”

“…The site 1 ligand binding interaction is similar to the previous insulin:IR and IGF-I:IGF-1R structures [ 64 , 69 , 70 ]. The IGF-II molecule contacts the L1, L2, αCT’, and FnIII-1’ domains within the head region of the receptor ( Figure 4 c) [ 63 ]. The L1-CR + (αCT’) module folds to the top of the receptor, permitting sparse interactions between IGF-II and the membrane-distal loops of FnIII-1’, facilitated by an outward rotation of domain L2 from its location in the apo ectodomain.…”

“…The B chain of IGF-II is stabilized by an interaction between IGF-II residue Arg30 and the hydroxyl group of IGF-1R residue Tyr28 and possibly a salt bridge between IGF-II residue Arg38 and IGF-1R residue Glu305. The ligand forms a ‘clip’ on the extended αCT helix in the active conformation, stabilizing a tight interaction between L1-CR-L2 and αCT’ with only sparse interactions between the ligand and FnIII-1’ ( Figure 4 c) [ 63 ].…”

“…This overall J-shaped conformation that brings the FnIII stalks together was seen previously in the Weis et al insulin:IR and Li et al IGF-I:IGF-1R studies [ 62 , 64 ]. The IGF-II:IGF-1R complex structure [ 63 ] was determined using a similar leucine-zippered receptor (IGF-1RZip) to that of the insulin receptor used in the Weis et al study [ 62 ]. The general topology of IGF-1RZip:IGF-II and IRZip:insulin structures also reflects that of the recently reported holoIGF-1R:IGF-I structure [ 64 ], providing further evidence that this is the common activated conformation.…”