|3up1, resolution 2.15Å ()|
|Ligands:||, , , ,|
|Gene:||IL7R (Homo sapiens)|
Crystal structure of the unliganded human interleukin-7 receptor extracellular domain
We report here an unliganded receptor structure in the common gamma-chain (gamma(c)) family of receptors and cytokines. The crystal structure of the unliganded form of the interleukin-7 alpha receptor (IL-7Ralpha) extracellular domain (ECD) at 2.15 A resolution reveals a homodimer forming an "X" geometry looking down onto the cell surface with the C termini of the two chains separated by 110 A and the dimer interface comprising residues critical for IL-7 binding. Further biophysical studies indicate a weak association of the IL-7Ralpha ECDs but a stronger association between the gamma(c)/IL-7Ralpha ECDs, similar to previous studies of the full-length receptors on CD4(+) T cells. Based on these and previous results, we propose a molecular mechanism detailing the progression from the inactive IL-7Ralpha homodimer and IL-7Ralpha-gamma(c) heterodimer to the active IL-7-IL-7Ralpha-gamma(c) ternary complex whereby the two receptors undergo at least a 90 degrees rotation away from the cell surface, moving the C termini of IL-7Ralpha and gamma(c) from a distance of 110 A to less than 30 A at the cell surface. This molecular mechanism can be used to explain recently discovered IL-7- and gamma(c)-independent gain-of-function mutations in IL-7Ralpha from B- and T-cell acute lymphoblastic leukemia patients. The mechanism may also be applicable to other gamma(c) receptors that form inactive homodimers and heterodimers independent of their cytokines.
Structural reorganization of the interleukin-7 signaling complex., McElroy CA, Holland PJ, Zhao P, Lim JM, Wells L, Eisenstein E, Walsh ST, Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2503-8. Epub 2012 Jan 30. PMID:22308406
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[IL7RA_HUMAN] Defects in IL7R are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-positive (T(-)B(+)NK(+) SCID) [MIM:608971]. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.[:] Genetic variations in IL7R are a cause of susceptibility to multiple sclerosis type 3 (MS3) [MIM:612595]. A multifactorial, inflammatory, demyelinating disease of the central nervous system. Sclerotic lesions are characterized by perivascular infiltration of monocytes and lymphocytes and appear as indurated areas in pathologic specimens (sclerosis in plaques). The pathological mechanism is regarded as an autoimmune attack of the myelin sheat, mediated by both cellular and humoral immunity. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia and bladder dysfunction. Genetic and environmental factors influence susceptibility to the disease. Note=A polymorphism at position 244 strongly influences susceptibility to multiple sclerosis. Overtransmission of the major 'C' allele coding for Thr-244 is detected in offspring affected with multiple sclerosis. In vitro analysis of transcripts from minigenes containing either 'C' allele (Thr-244) or 'T' allele (Ile-244) shows that the 'C' allele results in an approximately two-fold increase in the skipping of exon 6, leading to increased production of a soluble form of IL7R. Thus, the multiple sclerosis associated 'C' risk allele of IL7R would probably decrease membrane-bound expression of IL7R. As this risk allele is common in the general population, some additional triggers are probably required for the development and progression of MS.
[IL7RA_HUMAN] Receptor for interleukin-7. Also acts as a receptor for thymic stromal lymphopoietin (TSLP).
About this Structure
- McElroy CA, Holland PJ, Zhao P, Lim JM, Wells L, Eisenstein E, Walsh ST. Structural reorganization of the interleukin-7 signaling complex. Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2503-8. Epub 2012 Jan 30. PMID:22308406 doi:10.1073/pnas.1116582109
- ↑ Puel A, Ziegler SF, Buckley RH, Leonard WJ. Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet. 1998 Dec;20(4):394-7. PMID:9843216 doi:10.1038/3877
- ↑ Schmutz J, Martin J, Terry A, Couronne O, Grimwood J, Lowry S, Gordon LA, Scott D, Xie G, Huang W, Hellsten U, Tran-Gyamfi M, She X, Prabhakar S, Aerts A, Altherr M, Bajorek E, Black S, Branscomb E, Caoile C, Challacombe JF, Chan YM, Denys M, Detter JC, Escobar J, Flowers D, Fotopulos D, Glavina T, Gomez M, Gonzales E, Goodstein D, Grigoriev I, Groza M, Hammon N, Hawkins T, Haydu L, Israni S, Jett J, Kadner K, Kimball H, Kobayashi A, Lopez F, Lou Y, Martinez D, Medina C, Morgan J, Nandkeshwar R, Noonan JP, Pitluck S, Pollard M, Predki P, Priest J, Ramirez L, Retterer J, Rodriguez A, Rogers S, Salamov A, Salazar A, Thayer N, Tice H, Tsai M, Ustaszewska A, Vo N, Wheeler J, Wu K, Yang J, Dickson M, Cheng JF, Eichler EE, Olsen A, Pennacchio LA, Rokhsar DS, Richardson P, Lucas SM, Myers RM, Rubin EM. The DNA sequence and comparative analysis of human chromosome 5. Nature. 2004 Sep 16;431(7006):268-74. PMID:15372022 doi:10.1038/nature02919
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- ↑ Roifman CM, Zhang J, Chitayat D, Sharfe N. A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood. 2000 Oct 15;96(8):2803-7. PMID:11023514
- ↑ Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, Caillier SJ, Ban M, Goris A, Barcellos LF, Lincoln R, McCauley JL, Sawcer SJ, Compston DA, Dubois B, Hauser SL, Garcia-Blanco MA, Pericak-Vance MA, Haines JL. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet. 2007 Sep;39(9):1083-91. Epub 2007 Jul 29. PMID:17660817 doi:10.1038/ng2103