Biology Reference
In-Depth Information
Structural basis for the signal transduction of
erythropoietin
Timothy Osslund and Rashid Syed
Amgen Inc., One Amgen Center Drive, M/S 14-2-B, Thousand Oaks, California 91320, USA
Introduction
The structures of recombinant human erythropoietin (rHuEPO), erythropoietin
receptor (EPOR), and several novel peptides have been extensively studied
using a variety of methods including X-ray crystallography and nuclear mag-
netic resonance (NMR) [1, 2]. EPOR has been classified as a member of the
class 1 cytokine receptor super-family [3, 4], and is activated when EPO binds
to the extracellular portion of the receptor causing oligomerization [5]. The
dimerization of the extracellular portion of the receptor induces tyrosine
kinase proteins associated within the cytoplasmic side of the receptor to initi-
ate the signal transduction events, which eventually cause the committed ery-
throid colony-forming units (CFU-E) progenitor cells to mature into red blood
cells [6] (Fig. 1).
Studies on novel molecules, which cause two EPOR to form a dimer, have
shown that EPOR is promiscuous, as a variety of structurally unrelated mole-
cules can bind and activate the receptor. This oligomerization of the EPOR can
be caused by an engineered extracellular disulfide bond in EPOR that can
stimulate constitutive signal transduction [7]. Antibodies with epitopes that
react with the extracellular domain of EPOR also stimulate EPOR [8], as well
as several different peptides that show both agonist as well as antagonist activ-
ity [9-12]. In addition to rHuEPO, a novel hyperglycosylated form of EPO
(darbepoetin alfa) has shown activation of EPOR with improved pharmaco-
logic properties. The common modality for all the molecules that cause signal
transduction is that they all result in the formation of an EPOR dimer. It was
initially speculated that EPO functioned mechanistically as a cross-linker that
brings the intracellular portion of EPOR into close proximity, producing the
signal transduction events that eventually allow the cell to mature into a red
blood cell. Recent data, however, suggests that EPOR may initially form a
dimer on the cell surface [13], and that the function of EPO is to provide the
proper orientation outside the cell,thereby allowing the intracellular kinases to
be in the precise geometry for biologic activity.
