Activity-dependent conformational transitions of the insulin receptor–related receptor

Abstract

The insulin receptor (IR), insulin-like growth factor 1 receptor (IGF-1R), and insulin receptor-related receptor (IRR) form a mini family of predimerized receptor-like tyrosine kinases. IR and IGF-1R bind to their peptide agonists triggering metabolic and cell growth responses. In contrast, IRR, despite sharing with them a strong sequence homology, has no peptide-like agonist but can be activated by mildly alkaline media. The spatial structure and activation mechanisms of IRR have not been established yet. The present work represents the first account of a structural analysis of a predimerized receptor-like tyrosine kinase by high-resolution atomic force microscopy in their basal and activated forms. Our data suggest that in neutral media, inactive IRR has two conformations, where one is symmetrical and highly similar to the inactive Λ/U-shape of IR and IGF-1R ectodomains, whereas the second is drop-like and asymmetrical resembling the IRR ectodomain in solution. We did not observe complexes of IRR intracellular catalytic domains of the inactive receptor forms. At pH 9.0, we detected two presumably active IRR conformations, Γ-shaped and T-shaped. Both of conformations demonstrated formation of the complex of their intracellular catalytic domains responsible for autophosphorylation. The existence of two active IRR forms correlates well with the previously described positive cooperativity of the IRR activation. In conclusion, our data provide structural insights into the molecular mechanisms of alkali-induced IRR activation under mild native conditions that could be valuable for interpretation of results of IR and IGF-IR structural studies.

The Ambiguity Issue in Solving Inverse Problems of Small-Angle Scattering: A Consistent Approach Using an Insulin Receptor-Related Receptor as an Example. Methods for Interpreting SAXS Data

“…It was concluded that conformational rearrangements occur not only at the local level, as previously assumed [13], but also significantly change the overall shape of the ectodomain. The data obtained correspond to the conclusions of a recently published work, where a variety of forms of a full-size receptor similar to the insulin receptor was shown by atomic force microscopy [36].…”

Diversity of Structural, Dynamic, and Environmental Effects Explain a Distinctive Functional Role of Transmembrane Domains in the Insulin Receptor Subfamily

“…As noted above, the relatively hydrophilic surface regions ( Figure 2 A), which may serve as the potential specific patterns for TMD dimerization [ 39 , 40 ], can be identified in the TMD of each member of the insulin receptor subfamily. As revealed by recent structural studies of full-length receptors from this group [ 15 , 16 , 18 , 19 , 20 , 21 , 22 ], upon receptor activation, their TMD helices self-associate apparently via the N-terminal parts, as is typical for RTKs [ 39 , 40 , 43 , 44 ]. The N-terminal hydrophilic (polar) regions as potential dimerization motifs [ 39 , 40 ] adjacent to intramembrane prolines could be formed only in straight conformations of TMD helices, as demonstrated by us for IRRtm ( Figure 2 A,C) and previously proposed for IGF1R [ 29 ].…”

“…These states are characterized by small distances between the fibronectin domains and TMDs of the receptors. As it would be expected from the high sequence homology within the subfamily, IRR-ECD undergoes similar conformational transitions [ 22 ]. An additional “drop-like” shape of IRR-ECD with a short distance between the two membrane-proximal FnIII-3 domains was also described [ 17 , 22 ].…”

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

“…On the other hand, little is known about the IRR, despite the close homology with the IGF1R and IR. No peptide or protein agonist have been so far identified but recent studies demonstrated that the IRR is an alkaline extracellular pH sensor with a role in the regulation of the acid-base balance [13,23,24].…”