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Abstract
The receptor tyrosine kinase superfamily comprises many cell-surface receptors including the insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF1R) that are constitutively homodimeric transmembrane glycoproteins. Therefore, these receptors require ligand-triggered domain rearrangements rather than receptor dimerization for activation. Specifically, binding of peptide ligands to receptor ectodomains transduces signals across the transmembrane domains for trans-autophosphorylation in cytoplasmic kinase domains. The molecular details of these processes are poorly understood in part due to the absence of structures of full-length receptors. Using MD simulations and enhanced conformational sampling algorithms, we present all-atom structural models of peptides containing 51 residues from the transmembrane and juxtamembrane regions of IR and IGF1R. In our models, the transmembrane regions of both receptors adopt helical conformations with kinks at Pro961 (IR) and Pro941 (IGF1R), but the C-terminal residues corresponding to the juxtamembrane region of each receptor adopt unfolded and flexible conformations in IR as opposed to a helix in IGF1R. We also observe that the N-terminal residues in IR form a kinked-helix sitting at the membrane–solvent interface, while homologous residues in IGF1R are unfolded and flexible. These conformational differences result in a larger tilt-angle of the membrane-embedded helix in IGF1R in comparison to IR to compensate for interactions with water molecules at the membrane–solvent interfaces. Our metastable/stable states for the transmembrane domain of IR, observed in a lipid bilayer, are consistent with a known NMR structure of this domain determined in detergent micelles, and similar states in IGF1R are consistent with a previously reported model of the dimerized transmembrane domains of IGF1R. Our all-atom structural models suggest potentially unique structural organization of kinase domains in each receptor.
Highlights
Insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF1R) are homologous, ligandactivated, and constitutively homo-dimeric transmembrane glycoproteins of the receptor tyrosine kinase (RTK) superfamily [1]
We have previously shown that molecular dynamics (MD) simulations conducted in explicit solvent with all-atom structural models and enhanced sampling algorithms [53] are highly promising tools to understand conformational flexibility of receptor structures and their ligand-binding mechanisms [8, 54,55,56,57,58]
Using MD simulations combined with enhanced sampling algorithms, we have presented all-atom structural models of IR–transmembrane domain (TMD) and IGF1R–TMD in explicit membrane and solvent environments
Summary
Insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF1R) are homologous, ligandactivated, and constitutively homo-dimeric transmembrane glycoproteins of the receptor tyrosine kinase (RTK) superfamily [1]. A different “yo-yo” model of receptor activation was proposed by Ward et al [10] in which the ligand-induced conformational change releases kinase domains (for transphosphorylation) from an initially constrained position near the membrane. These studies do not directly support a common mechanism of activation of transmembrane cell-surface receptors [27]
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