Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist

Abstract

Lymphocystis disease virus-1 (LCDV-1) and several other Iridoviridae encode viral insulin/IGF-1 like peptides (VILPs) with high homology to human insulin and IGFs. Here we show that while single-chain (sc) and double-chain (dc) LCDV1-VILPs have very low affinity for the insulin receptor, scLCDV1-VILP has high affinity for IGF1R where it can antagonize human IGF-1 signaling, without altering insulin signaling. Consequently, scLCDV1-VILP inhibits IGF-1 induced cell proliferation and growth hormone/IGF-1 induced growth of mice in vivo. Cryo-electron microscopy reveals that scLCDV1-VILP engages IGF1R in a unique manner, inducing changes in IGF1R conformation that led to separation, rather than juxtaposition, of the transmembrane segments and hence inactivation of the receptor. Thus, scLCDV1-VILP is a natural peptide with specific antagonist properties on IGF1R signaling and may provide a new tool to guide development of hormonal analogues to treat cancers or metabolic disorders sensitive to IGF-1 without affecting glucose metabolism.

The correlation between non-traumatic avascular necrosis of femoral head and insulin-like growth factor-1 and bone metabolism markers

“…Among these bone metabolism markers, IGF-1, β-CTX and 25(OH)D were found closely related with N-ANFH, while N-MID, T-PINP and Parathormone were shown less signi cant for N-ANFH. IGF-1 is found to be a single-chain polypeptide encoded by IGF-1 gene [19]. IGF-1 can regulate bone homeostasis and maintain skeletal architecture by its bone morphogenetic effects [20].…”

Recombinant Insulin-Like Growth Factor 1 Dimers: Receptor Binding Affinities and Activation Abilities

“…S3) is probably not sufficient to allow efficient binding to both Sites 1 and 1’, similarly to insulins in Fig. 1 A or IGF-like peptides in 7U23.pdb structure by Moreau et al (Moreau et al 2022 ), but should not preclude binding to Sites 1 and 2 as was the case for the B29-B29-linked antagonistic insulin dimers and their binding to IR (Wu et al 2022 ). The lack of antagonism can be explained in different ways: the dimer does not bind to Site 1 and Site 2 simultaneously because the inherent properties of IGF-1R do not allow this in principle or the dimer binds to both sites simultaneously, but the length of its linker allows full structural transition and activation of the receptor.…”

“…However, two molecules of the hormone were found bound to the IGF-1R in crystals soaked with IGF-1, but this was considered as an artifact caused by constrains of the crystal lattice (Xu et al 2018 ). Very recently, Moreau et al (Moreau et al 2022 ) solved cryo-EM structure (7U23.pdb) of IGF-1R construct in a pseudo-two-fold-symmetric arrangement of the receptor domains with two molecules of IGF-like viral peptide symmetrically bound to L1 domain/a-CT peptide segments (part of Site 1). Remarkably, the viral peptide behaves as natural IGF-1R antagonist and its antagonistic properties are associated with its unique C-domain sequence and Ser8 residue in the B-domain (Zhang et al 2021 ), which do not allow the viral peptide to engage membrane distant part of FnIII-1’ domain (another part of Site 1).…”

Insulin receptor Arg717 and IGF-1 receptor Arg704 play a key role in ligand binding and in receptor activation

“…3018). An anti-actin (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) antibody (Sigma-Aldrich, cat. no.…”

“…The significance of differences in autophosphorylation ability of the receptor mutants and wild-type receptors was calculated, using one-way analysis of variance with Dunnett's test comparing the autophosphorylation of mutated receptors with the background signal of nonstimulated cells or with the wild-type receptor. An anti-actin (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) antibody (Sigma-Aldrich, cat. no.…”