Delineation of the IGF-II C domain elements involved in binding and activation of the IR-A, IR-B and IGF-IR

Henderson, S.; Brierley, Gemma V.; Surinya, Kathy H.; Priebe, Ilka; Catcheside, David; Wallace, John C.; Forbes, Briony E.; Cosgrove, Leah

doi:10.1016/j.ghir.2014.09.004

Cited by 15 publications

(19 citation statements)

References 34 publications

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“…Lack of electrostatic complementarity between IR and IGFs does not therefore appear to be the primary reason for the reduced affinity of IGFs for IR, both with respect to that of insulin for IR and with respect to that of the IGFs for IGF-1R (Denley et al, 2004). Instead, we propose that the higher affinity of IGF-II for both IR-A and IR-B with respect to the corresponding affinities of IGF-I to IR-A and IR-B (Denley et al, 2004;Henderson et al, 2014) may be attributable at least in part to the reduced size of the IGF-II C domain with respect to that of IGF-I (Figure 1C), allowing easier steric accommodation within the volume between the L1-b 2 surface and that of the opposing CR domain Table 1) and in the apo-mIR structure (purple) presented here. of IR.…”

Section: Discussionmentioning

confidence: 64%

“…of IR. However, our structure is unable to reveal additional interaction(s) of bound IGF with receptor domains absent from the microreceptor construct and we thus cannot rule out C domain sequence-specific modulation of IGF affinity within that context (Henderson et al, 2014). Interestingly, single-chain insulin/IGF C domain hybrid ligands can bind both IR and IGF-1R with high affinity (Kristensen et al, 1995;Wang et al, 2000) and possess ten times the growth-promoting activities of insulin on a breast cancer cell line (Wang et al, 2000).…”

Section: Discussionmentioning

confidence: 82%

“…Likewise, the IGF-I D domain residues Lys65 and/or Lys68 (while disordered here) also do not lie in the immediate vicinity of the IR residues Arg270 and Arg271 ( Figure 3B). We note further that the affinities of IGF-II for both IR-A and IR-B are correspondingly higher than affinities of IGF-I for IR-A and IR-B (Denley et al, 2004;Henderson et al, 2014), despite the additional two arginines in the C domain of IGF-II with respect to that of IGF-I ( Figure 1C). Lack of electrostatic complementarity between IR and IGFs does not therefore appear to be the primary reason for the reduced affinity of IGFs for IR, both with respect to that of insulin for IR and with respect to that of the IGFs for IGF-1R (Denley et al, 2004).…”

Section: Discussionmentioning

confidence: 83%

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Structural Congruency of Ligand Binding to the Insulin and Insulin/Type 1 Insulin-like Growth Factor Hybrid Receptors

et al. 2015

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The homodimeric insulin and type 1 insulin-like growth factor receptors (IR and IGF-1R) share a common architecture and each can bind all three ligands within the family: insulin and insulin-like growth factors I and II (IGF-I and IFG-II). The receptor monomers also assemble as heterodimers, the primary ligand-binding sites of which each comprise the first leucine-rich repeat domain (L1) of one receptor type and an α-chain C-terminal segment (αCT) of the second receptor type. We present here crystal structures of IGF-I bound to such a hybrid primary binding site and of a ligand-free version of an IR αCT peptide bound to an IR L1 plus cysteine-rich domain construct (IR310.T). These structures, refined at 3.0-Å resolution, prove congruent to respective existing structures of insulin-complexed IR310.T and the intact apo-IR ectodomain. As such, they provide key missing links in the emerging, but sparse, repertoire of structures defining the receptor family.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 83%

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Structural Congruency of Ligand Binding to the Insulin and Insulin/Type 1 Insulin-like Growth Factor Hybrid Receptors

et al. 2015

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“…We hypothesized that such modifications may negatively affect the hormone's binding potency toward IR-A while enhancing the binding affinity for IGF-1R. Moreover, there are no reported analogs with the mutation of Ser 29 in IGF-II, and there are only a few studies regarding alterations in the C-domain ( 57 , 59 ).…”

Section: Discussionmentioning

confidence: 99%

Probing Receptor Specificity by Sampling the Conformational Space of the Insulin-like Growth Factor II C-domain

Hexnerova

Křížková

Fábry

et al. 2016

Journal of Biological Chemistry

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Insulin and insulin-like growth factors I and II are closely related protein hormones. Their distinct evolution has resulted in different yet overlapping biological functions with insulin becoming a key regulator of metabolism, whereas insulin-like growth factors (IGF)-I/II are major growth factors. Insulin and IGFs cross-bind with different affinities to closely related insulin receptor isoforms A and B (IR-A and IR-B) and insulin-like growth factor type I receptor (IGF-1R). Identification of structural determinants in IGFs and insulin that trigger their specific signaling pathways is of increasing importance in designing receptor-specific analogs with potential therapeutic applications. Here, we developed a straightforward protocol for production of recombinant IGF-II and prepared six IGF-II analogs with IGF-I-like mutations. All modified molecules exhibit significantly reduced affinity toward IR-A, particularly the analogs with a Pro-Gln insertion in the C-domain. Moreover, one of the analogs has enhanced binding affinity for IGF-1R due to a synergistic effect of the Pro-Gln insertion and S29N point mutation. Consequently, this analog has almost a 10-fold higher IGF-1R/IR-A binding specificity in comparison with native IGF-II. The established IGF-II purification protocol allowed for cost-effective isotope labeling required for a detailed NMR structural characterization of IGF-II analogs that revealed a link between the altered binding behavior of selected analogs and conformational rearrangement of their C-domains.

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“…Previous experimental studies have revealed the critical role of the C domain and, to a lesser extent, the D domain of the IGFs for insulin receptor (IR) and IGF-1R binding specificity and activation [1,4,17–19]. Dentley et al have shown that IGF-I and IGF-II chimeras with swapped C and/or D domains perform with similar binding affinities to those of the donor molecules, and an IGF-I chimera comprising IGF-II C domain induced autophosphorylation of the IR-A and IR-B (B isoform of the insulin receptor) and activated signaling pathways in a similar way to IGF-II [3].…”

Section: Introductionmentioning

confidence: 99%

Elucidating the Activation Mechanism of the Insulin-Family Proteins with Molecular Dynamics Simulations

2016

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The insulin-family proteins bind to their own receptors, but insulin-like growth factor II (IGF-II) can also bind to the A isoform of the insulin receptor (IR-A), activating unique and alternative signaling pathways from those of insulin. Although extensive studies of insulin have revealed that its activation is associated with the opening of the B chain-C terminal (BC-CT), the activation mechanism of the insulin-like growth factors (IGFs) still remains unknown. Here, we present the first comprehensive study of the insulin-family proteins comparing their activation process and mechanism using molecular dynamics simulations to reveal new insights into their specificity to the insulin receptor. We have found that all the proteins appear to exhibit similar stochastic dynamics in their conformational change to an active state. For the IGFs, our simulations show that activation involves two opening locations: the opening of the BC-CT section away from the core, similar to insulin; and the additional opening of the BC-CT section away from the C domain. Furthermore, we have found that these two openings occur simultaneously in IGF-I, but not in IGF-II, where they can occur independently. This suggests that the BC-CT section and the C domain behave as a unified domain in IGF-I, but as two independent domains in IGF-II during the activation process, implying that the IGFs undergo different activation mechanisms for receptor binding. The probabilities of the active and inactive states of the proteins suggest that IGF-II is hyperactive compared to IGF-I. The hinge residue and the hydrophobic interactions in the core are found to play a critical role in the stability and activity of IGFs. Overall, our simulations have elucidated the crucial differences and similarities in the activation mechanisms of the insulin-family proteins, providing new insights into the molecular mechanisms responsible for the observed differences between IGF-I and IGF-II in receptor binding.

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Delineation of the IGF-II C domain elements involved in binding and activation of the IR-A, IR-B and IGF-IR

Cited by 15 publications

References 34 publications

Structural Congruency of Ligand Binding to the Insulin and Insulin/Type 1 Insulin-like Growth Factor Hybrid Receptors

Structural Congruency of Ligand Binding to the Insulin and Insulin/Type 1 Insulin-like Growth Factor Hybrid Receptors

Probing Receptor Specificity by Sampling the Conformational Space of the Insulin-like Growth Factor II C-domain

Elucidating the Activation Mechanism of the Insulin-Family Proteins with Molecular Dynamics Simulations

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