Visualization of Ligand-Bound Ectodomain Assembly in the Full-Length Human IGF-1 Receptor by Cryo-EM Single-Particle Analysis

Zhang, Xi; Yu, Dongke; Sun, Jingchuan; Wu, Yujie; Gong, Jingshan; Li, Xuemei; Liu, Li; Liu, Shan; Li, Jianbo; Wu, Yi; Li, Dongyang; Ma, Yinping; Xu, Han; Zhu, Yanhua; Wu, Zhaolong; Wang, Yihua; Ouyang, Qi; Wang, Tao

doi:10.1016/j.str.2020.03.007

Cited by 28 publications

(58 citation statements)

References 39 publications

(73 reference statements)

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“…5c). A lack of rigidity in the linkage between the extracellular module and the transmembrane helices is emerging as a common feature in receptor tyrosine kinases 10,[22][23][24] , and the mechanism we have defined could potentially be utilized by other receptor tyrosine kinases to generate ligand-specific signaling outputs 37 .…”

Section: Discussionmentioning

confidence: 99%

A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor

Huang

Ognjenović

Karandur

et al. 2020

Preprint

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The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-a (TGF-α), to the initiation of intracellular signaling pathways1–3. EGFR binds to EGF and TGF-α with similar affinity but exhibits biased agonism, generating different signals from these ligands4–6. The mechanistic basis for this phenomenon remains unclear. We now present cryo-EM analyses of human EGFR bound to EGF and TGF-α. We find, unexpectedly, that the extracellular module adopts an ensemble of dimeric conformations when bound to either EGF or TGF-α. The two extreme states of this ensemble represent distinct ligand-bound quaternary structures in which the membrane-proximal ends of the extracellular module are either juxtaposed or separated. EGF and TGF-α differ in their ability to maintain the conformation with the membrane-proximal ends of the extracellular module separated, and this conformation is stabilized preferentially by an oncogenic EGFR mutation. Close proximity of the transmembrane helices at the junction with the extracellular module is known to increase EGFR activity. Our results show how EGFR can couple the binding of different ligands to differential modulation of this proximity, thereby providing a mechanism for the generation of biased agonism in this receptor family.

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Section: Discussionmentioning

confidence: 99%

A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor

Huang

Ognjenović

Karandur

et al. 2020

Preprint

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“…IGF-1 is structurally related to insulin. It consists of 70 amino acids in a single chain with three intramolecular bridges and has a molecular weight of 7,649 Daltons [35,36]. This growth factor is produced by GH-stimulated hepatocytes (the main source of circulating IGF-1) and by all nonhepatic tissues where it acts in a paracrine/autocrine fashion [1].…”

Section: Insulin-like Growth Factor-1 (Igf-1)mentioning

confidence: 99%

“…IGF-1 is the most abundant growth factor in bone matrix [33] where it is synthesized by osteoblast mesenchymal precursors, mature osteoblasts, osteoclasts and osteocytes [1,35,36]. Osteoblasts also produce all the IGFBPs [39].…”

Section: Igf-1 and Bone Homeostasismentioning

confidence: 99%

Microgravity, Bone Homeostasis, and Insulin-like Growth Factor-1

Smith¹

2020

Preprint

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Astronauts at are risk of losing 1.0 – 1.5% of their bone mass for every month they spend in space despite their adherence to high impact exercise training programs designed to preserve the musculoskeletal system. This article reviews the basics of bone formation and resorption and details how exposure to microgravity or simulated microgravity affects the structure and function of osteoblasts, osteocytes, osteoclasts, and their mesenchymal and hematologic stem cell precursors. It details the critical roles that insulin-like growth facor-1 and its receptor IGFR1 play in maintaining bone homeostasis and how exposure of bone cells to microgravity affects the function of these growth factors. Lastly, it discusses the potential of tumor necrosis factor-related apoptosis-inducing ligand, syncytin-A, and sclerostin inhibitors and recombinant IGF-1 as a bone-saving treatment for astronauts in space and during their colonization of the Moon.

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“…IGF-1 is structurally related to insulin. It consists of 70 amino acids in a single chain with three intramolecular bridges and has a molecular weight of 7649 Daltons [41,42]. This growth factor is produced by GH-stimulated hepatocytes (the main source of circulating IGF-1) and by all non-hepatic tissues where it acts in a paracrine/autocrine fashion [7].…”

Section: Insulin-like Growth Factor-1 (Igf-1)mentioning

confidence: 99%

“…Binding of one IGF-1 molecule is sufficient to break the autoinhibited state of IGF-1R and initiate receptor activation. This results in the activation of a variety of intracellular transduction cascades including phosphatidlyinositol-3 kinase (PI3K) and its downstream target, mammalian target of rapamycin (mTOR) [41,42]. Recently, IGF-IR has been shown to have extensive cross-talk with many other receptors and can function as an RTK/GPCR hybrid.…”

Section: Insulin-like Growth Factor-1 Receptor (Igf-1r)mentioning

confidence: 99%

Microgravity, Bone Homeostasis, and Insulin-Like Growth Factor-1

Smith¹

2020

Applied Sciences

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Astronauts at are risk of losing 1.0–1.5% of their bone mass for every month they spend in space despite their adherence to high impact exercise training programs and diets high in nutrients, potassium, calcium, and vitamin D, all designed to preserve the skeletal system. This article reviews the basics of bone formation and resorption and details how exposure to microgravity or simulated microgravity affects the structure and function of osteoblasts, osteocytes, osteoclasts, and their mesenchymal and hematologic stem cell precursors. It details the critical roles that insulin-like growth factor-1 and its receptor insulin-like growth factor-1 receptor (GFR1) play in maintaining bone homeostasis and how exposure of bone cells to microgravity affects the function of these growth factors. Lastly, it discusses the potential of tumor necrosis factor-related apoptosis-inducing ligand, syncytin-A, sclerostin inhibitors and recombinant IGF-1 as a bone-saving treatment for astronauts in space and during their colonization of the Moon.

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Visualization of Ligand-Bound Ectodomain Assembly in the Full-Length Human IGF-1 Receptor by Cryo-EM Single-Particle Analysis

Abstract: Highlights d Purification of biologically functional human IGF-1R in fulllength d Cryo-EM structures of insulin or IGF-1 bound human IGF-1R d Hormone induces the formation of active IGF-1R assembly

Cited by 28 publications

References 39 publications

A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor

A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor

Microgravity, Bone Homeostasis, and Insulin-like Growth Factor-1

Microgravity, Bone Homeostasis, and Insulin-Like Growth Factor-1

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