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@ARTICLE{Schillinger:836813,
author = {Schillinger, Oliver and Panwalkar, Vineet and Strodel,
Birgit and Dingley, Andrew},
title = {{M}olecular {D}ynamics {S}imulations {R}eveal {K}ey {R}oles
of the {I}nterleukin-6 {A}lpha {R}eceptor in the {A}ssembly
of the {H}uman {I}nterleukin-6 {R}eceptor {C}omplex},
journal = {The journal of physical chemistry letters},
volume = {121},
issn = {1948-7185},
address = {Washington, DC},
publisher = {ACS},
reportid = {FZJ-2017-05855},
pages = {8113-8122},
year = {2017},
abstract = {Human interleukin-6 (hIL-6) is a pleiotropic cytokine with
three distinct receptor epitopes, termed sites I, II and
III, which function to assemble a signaling complex. hIL-6
signals via a glycoprotein 130 (gp130) homodimer after
initially forming a heterodimer with the non-signaling
α-receptor (IL-6Rα). The molecular description of the
assembly of the hIL-6 signaling complex remains elusive
because available structures provide descriptions of hIL-6
in its free and fully bound receptor forms, but not for
intermediate steps that are crucial in the stepwise assembly
of the signaling complex. In this report, molecular dynamics
simulations provide atomic details describing the functional
role of the initial hIL-6/IL-6Rα complex in facilitating
subsequent interactions with gp130, which have not been
previously shown. IL-6Rα binding to hIL-6 rigidifies the
flexible N-terminus of the hIL-6 AB-loop through
interactions with the D2 domain of IL-6Rα. This
rigidification combined with repositioning of residues
involved in gp130 receptor recognition promotes gp130
binding at site III. Binding of gp130 receptors at sites II
and III is coupled with the release of the hIL-6 N-terminal
AB-loop interaction and a pivoting of IL-6Rα around the
hIL-6 helix bundle to the state of the hIL-6/IL-6Rα/gp130
complex.},
cin = {ICS-6},
ddc = {530},
cid = {I:(DE-Juel1)ICS-6-20110106},
pnm = {551 - Functional Macromolecules and Complexes (POF3-551)},
pid = {G:(DE-HGF)POF3-551},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000409394900011},
doi = {10.1021/acs.jpcb.7b05732},
url = {https://juser.fz-juelich.de/record/836813},
}