4y5v

From Proteopedia

Jump to: navigation, search

Diabody 305 complex with EpoR

Structural highlights

4y5v is a 9 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:GOL, PEG, PGE
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

EPOR_HUMAN Defects in EPOR are the cause of familial erythrocytosis type 1 (ECYT1) [MIM:133100. ECYT1 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated hemoglobin and hematocrit, hypersensitivity of erythroid progenitors to erythropoietin, erythropoietin low serum levels, and no increase in platelets nor leukocytes. It has a relatively benign course and does not progress to leukemia.[1] [2] [3]

Function

EPOR_HUMAN Receptor for erythropoietin. Mediates erythropoietin-induced erythroblast proliferation and differentiation. Upon EPO stimulation, EPOR dimerizes triggering the JAK2/STAT5 signaling cascade. In some cell types, can also activate STAT1 and STAT3. May also activate the LYN tyrosine kinase. Isoform EPOR-T acts as a dominant-negative receptor of EPOR-mediated signaling.

Publication Abstract from PubMed

Most cell-surface receptors for cytokines and growth factors signal as dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to "tune" signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Erythropoietin (EPO) and its receptor (EpoR), to dimerize EpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism, and structures of these DA/EpoR complexes differed in EpoR dimer orientation and proximity. Diabodies also elicited biased or differential activation of signaling pathways and gene expression profiles compared to EPO. Non-signaling diabodies inhibited proliferation of erythroid precursors from patients with a myeloproliferative neoplasm due to a constitutively active JAK2V617F mutation. Thus, intracellular oncogenic mutations causing ligand-independent receptor activation can be counteracted by extracellular ligands that re-orient receptors into inactive dimer topologies. This approach has broad applications for tuning signaling output for many dimeric receptor systems.

Tuning Cytokine Receptor Signaling by Re-orienting Dimer Geometry with Surrogate Ligands.,Moraga I, Wernig G, Wilmes S, Gryshkova V, Richter CP, Hong WJ, Sinha R, Guo F, Fabionar H, Wehrman TS, Krutzik P, Demharter S, Plo I, Weissman IL, Minary P, Majeti R, Constantinescu SN, Piehler J, Garcia KC Cell. 2015 Mar 12;160(6):1196-208. doi: 10.1016/j.cell.2015.02.011. Epub 2015 Feb, 26. PMID:25728669[4]

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

Loading citation details..
Citations
28 reviews cite this structure
Conformational Basis of G Protein-Coupled Receptor Signaling Versatility.
Wingler et al. (2020)
27 more
72 other articles
No citations found

See Also

References

  1. ↑ de la Chapelle A, Traskelin AL, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4495-9. PMID:8506290
  2. ↑ Sokol L, Prchal JF, D'Andrea A, Rado TA, Prchal JT. Mutation in the negative regulatory element of the erythropoietin receptor gene in a case of sporadic primary polycythemia. Exp Hematol. 1994 May;22(5):447-53. PMID:8174675
  3. ↑ Le Couedic JP, Mitjavila MT, Villeval JL, Feger F, Gobert S, Mayeux P, Casadevall N, Vainchenker W. Missense mutation of the erythropoietin receptor is a rare event in human erythroid malignancies. Blood. 1996 Feb 15;87(4):1502-11. PMID:8608241
  4. ↑ Moraga I, Wernig G, Wilmes S, Gryshkova V, Richter CP, Hong WJ, Sinha R, Guo F, Fabionar H, Wehrman TS, Krutzik P, Demharter S, Plo I, Weissman IL, Minary P, Majeti R, Constantinescu SN, Piehler J, Garcia KC. Tuning Cytokine Receptor Signaling by Re-orienting Dimer Geometry with Surrogate Ligands. Cell. 2015 Mar 12;160(6):1196-208. doi: 10.1016/j.cell.2015.02.011. Epub 2015 Feb, 26. PMID:25728669 doi:http://dx.doi.org/10.1016/j.cell.2015.02.011

Contents


PDB ID 4y5v

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://proteopedia.org/wiki/index.php/4y5v"
Personal tools