Activation of the erythropoietin receptor by the gp55-P viral envelope protein is determined by a single amino acid in its transmembrane domain

被引:44
作者
Constantinescu, SN
Liu, XD
Beyer, W
Fallon, A
Shekar, S
Henis, YI
Smith, SO
Lodish, HF [1 ]
机构
[1] Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA
[2] Kenyon Coll, Dept Biol, Gambier, OH 43022 USA
[3] MIT, Dept Biol, Cambridge, MA 02139 USA
[4] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA
[5] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiochem, IL-69978 Tel Aviv, Israel
关键词
Epo receptor signaling; red cell formation; SFFV-gp55 env proteins; transmembrane coiled-coil interactions;
D O I
10.1093/emboj/18.12.3334
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The spleen focus forming virus (SFFV) gp55-P envelope glycoprotein specifically binds to and activates murine erythropoietin receptors (EpoRs) coexpressed in the same cell, triggering proliferation of erythroid progenitors and inducing erythroleukemia. Here we demonstrate specific interactions between the single transmembrane domains of the two proteins that are essential for receptor activation. The human EpoR is not activated by gp55-P but by mutation of a single amino acid, L238, in its transmembrane sequence to its murine counterpart serine, resulting in its ability to be activated. The converse mutation in the murine EpoR (S238L) abolishes activation by gp55-P, Computational searches of interactions between the membrane-spanning segments of murine EpoR and gp55-P provide a possible explanation: the face of the EpoR transmembrane domain containing S238 is predicted to interact specifically,vith gp55-P but not gp55-A, a variant which is much less effective in activating the murine EpoR, Mutational studies on gp55-P M390, which is predicted to interact with S238, provide additional support for this model. Mutation of M390 to isoleucine, the corresponding residue in gp55-A, abolishes activation, but the gp55-P M390L mutation is fully functional. gp55-P is thought to activate signaling by the EpoR by inducing receptor oligomerization through interactions involving specific transmembrane residues.
引用
收藏
页码:3334 / 3347
页数:14
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