8av2

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Crystal structure for the FnIII module of mouse LEP-R in complex with the anti-LEP-R nanobody VHH-4.80

Structural highlights

8av2 is a 4 chain structure with sequence from Lama glama and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.75Å
Ligands:CSO, NAG, SO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LEPR_MOUSE Receptor for hormone LEP/leptin (Probable) (PubMed:11861497). On ligand binding, mediates LEP central and peripheral effects through the activation of different signaling pathways such as JAK2/STAT3 and MAPK cascade/FOS (PubMed:10799542, PubMed:11861497, PubMed:11923481, PubMed:25383904). In the hypothalamus, LEP acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones (PubMed:10660043, PubMed:12594516). In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic and affects innate and adaptive immunity (PubMed:11923481, PubMed:25383904). Control of energy homeostasis and melanocortin production (stimulation of POMC and full repression of AgRP transcription) is mediated by STAT3 signaling, whereas distinct signals regulate NPY and the control of fertility, growth and glucose homeostasis (PubMed:12594516). Involved in the regulation of counter-regulatory response to hypoglycemia by inhibiting neurons of the parabrachial nucleus (PubMed:25383904). Has a specific effect on T lymphocyte responses, differentially regulating the proliferation of naive and memory T-cells. Leptin increases Th1 and suppresses Th2 cytokine production (PubMed:9732873).[1] [2] [3] [4] [5] [6] [7] [8] May transport LEP across the blood-brain barrier. Binds LEP and mediates LEP endocytosis (PubMed:17620316, PubMed:20223942). Does not induce phosphorylation of and activate STAT3 (PubMed:11923481, PubMed:20223942).[9] [10] [11] Antagonizes Isoform A and isoform B-mediated LEP binding and endocytosis.[12]

Publication Abstract from PubMed

The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Intriguingly, the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms contributing to a mechanistic conundrum. Here we show by X-ray crystallography and cryo-EM that, in contrast to long-standing paradigms, Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry and demonstrate such Leptin-induced trimerization of LEP-R on living cells via single-molecule microscopy. In mediating these assemblies, Leptin undergoes drastic restructuring that activates its site III for binding to the Ig domain of an adjacent LEP-R. These interactions are abolished by mutations linked to obesity. Collectively, our study provides the structural and mechanistic framework for how evolutionarily conserved Leptin:LEP-R assemblies with 3:3 stoichiometry can engage distinct LEP-R isoforms to achieve signaling.

Mechanism of receptor assembly via the pleiotropic adipokine Leptin.,Tsirigotaki A, Dansercoer A, Verschueren KHG, Markovic I, Pollmann C, Hafer M, Felix J, Birck C, Van Putte W, Catteeuw D, Tavernier J, Fernando Bazan J, Piehler J, Savvides SN, Verstraete K Nat Struct Mol Biol. 2023 Apr;30(4):551-563. doi: 10.1038/s41594-023-00941-9. , Epub 2023 Mar 23. PMID:36959263[13]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. ↑ Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000 Jan 21;100(2):197-207. PMID:10660043 doi:10.1016/s0092-8674(00)81558-5
  2. ↑ Banks AS, Davis SM, Bates SH, Myers MG Jr. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem. 2000 May 12;275(19):14563-72. PMID:10799542 doi:10.1074/jbc.275.19.14563
  3. ↑ Hileman SM, Pierroz DD, Masuzaki H, Bjørbaek C, El-Haschimi K, Banks WA, Flier JS. Characterizaton of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity. Endocrinology. 2002 Mar;143(3):775-83. PMID:11861497 doi:10.1210/endo.143.3.8669
  4. ↑ Bahrenberg G, Behrmann I, Barthel A, Hekerman P, Heinrich PC, Joost HG, Becker W. Identification of the critical sequence elements in the cytoplasmic domain of leptin receptor isoforms required for Janus kinase/signal transducer and activator of transcription activation by receptor heterodimers. Mol Endocrinol. 2002 Apr;16(4):859-72. PMID:11923481 doi:10.1210/mend.16.4.0800
  5. ↑ Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, Myers MG Jr. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature. 2003 Feb 20;421(6925):856-9. PMID:12594516 doi:10.1038/nature01388
  6. ↑ Flak JN, Patterson CM, Garfield AS, D'Agostino G, Goforth PB, Sutton AK, Malec PA, Wong JT, Germani M, Jones JC, Rajala M, Satin L, Rhodes CJ, Olson DP, Kennedy RT, Heisler LK, Myers MG Jr. Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. Nat Neurosci. 2014 Dec;17(12):1744-1750. PMID:25383904 doi:10.1038/nn.3861
  7. ↑ Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature. 1998 Aug 27;394(6696):897-901. PMID:9732873 doi:10.1038/29795
  8. ↑ Allison MB, Myers MG Jr. 20 years of leptin: connecting leptin signaling to biological function. J Endocrinol. 2014 Oct;223(1):T25-35. PMID:25232147 doi:10.1530/JOE-14-0404
  9. ↑ Bahrenberg G, Behrmann I, Barthel A, Hekerman P, Heinrich PC, Joost HG, Becker W. Identification of the critical sequence elements in the cytoplasmic domain of leptin receptor isoforms required for Janus kinase/signal transducer and activator of transcription activation by receptor heterodimers. Mol Endocrinol. 2002 Apr;16(4):859-72. PMID:11923481 doi:10.1210/mend.16.4.0800
  10. ↑ Tu H, Kastin AJ, Hsuchou H, Pan W. Soluble receptor inhibits leptin transport. J Cell Physiol. 2008 Feb;214(2):301-5. PMID:17620316 doi:10.1002/jcp.21195
  11. ↑ Tu H, Hsuchou H, Kastin AJ, Wu X, Pan W. Unique leptin trafficking by a tailless receptor. FASEB J. 2010 Jul;24(7):2281-91. PMID:20223942 doi:10.1096/fj.09-143487
  12. ↑ Tu H, Kastin AJ, Hsuchou H, Pan W. Soluble receptor inhibits leptin transport. J Cell Physiol. 2008 Feb;214(2):301-5. PMID:17620316 doi:10.1002/jcp.21195
  13. ↑ Tsirigotaki A, Dansercoer A, Verschueren KHG, Marković I, Pollmann C, Hafer M, Felix J, Birck C, Van Putte W, Catteeuw D, Tavernier J, Fernando Bazan J, Piehler J, Savvides SN, Verstraete K. Mechanism of receptor assembly via the pleiotropic adipokine Leptin. Nat Struct Mol Biol. 2023 Mar 23. PMID:36959263 doi:10.1038/s41594-023-00941-9

Contents


PDB ID 8av2

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