8ez0
Cryo-EM structure of 4 insulins bound full-length mouse IR mutant with physically decoupled alpha CTs (C684S/C685S/C687S; denoted as IR-3CS) Symmetric conformationCryo-EM structure of 4 insulins bound full-length mouse IR mutant with physically decoupled alpha CTs (C684S/C685S/C687S; denoted as IR-3CS) Symmetric conformation
Structural highlights
DiseaseINS_HUMAN Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:176730.[1] [2] [3] [4] Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:125852. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.[5] Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:606176. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.[6] [7] Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:613370. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.[8] [9] [10] FunctionINS_HUMAN Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver. Publication Abstract from PubMedThe insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked homodimers in the apo-state; however, their ligand binding properties and the structures in the active state differ substantially. It has been proposed that the disulfide-linked C-terminal segment of alpha-chain (alphaCTs) of the IR and IGF1R control the cooperativity of ligand binding and regulate the receptor activation. Nevertheless, the molecular basis for the roles of disulfide-linked alphaCTs in IR and IGF1R activation are still unclear. Here, we report the cryo-EM structures of full-length mouse IGF1R/IGF1 and IR/insulin complexes with modified alphaCTs that have increased flexibility. Unlike the Gamma-shaped asymmetric IGF1R dimer with a single IGF1 bound, the IGF1R with the enhanced flexibility of alphaCTs can form a T-shaped symmetric dimer with two IGF1s bound. Meanwhile, the IR with non-covalently linked alphaCTs predominantly adopts an asymmetric conformation with four insulins bound, which is distinct from the T-shaped symmetric IR. Using cell-based experiments, we further showed that both IGF1R and IR with the modified alphaCTs cannot activate the downstream signaling potently. Collectively, our studies demonstrate that the certain structural rigidity of disulfide-linked alphaCTs is critical for optimal IR and IGF1R signaling activation. Molecular basis for the role of disulfide-linked alphaCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor.,Li J, Wu J, Hall C, Bai XC, Choi E Elife. 2022 Nov 22;11:e81286. doi: 10.7554/eLife.81286. PMID:36413010[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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