Science - 06.12.2019

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the complex and bidirectionally alters the
magnitude of gating modulation by CNIH3
( 26 ). Replacing A793 of M4 and F3 of CNIH3
with cysteine induced a disulfide cross-link,
further supporting the model that two resi-
dues interact (fig. S18). I hypothesize that the
binding site for the three phenylalanines (F3,
-5, and -8 of CNIH3) near the extracellular
surface of GluA2 dictates gating modula-
tion and is a potential target for drugs that
couldbeusedtocontroltheionchannel
activity of AMPARs. The detailed architecture
of the interaction interface suggests a possi-
bleroleforlipidsinregulatingtheassem-
bly or function of the complexes formed by


AMPAR and auxiliary subunits. The molec-
ular model of CNIH3 is likely to serve as a
reference for future investigations of the
biology of the cornichon family.

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Fig. 3. Binding interface and arrangements of lipids.(A) The densities that
surround the transmembrane helices have a characteristic appearance of
densities derived from lipid and detergents. The map LBD-TMD-C3lipid(see
materials and methods and fig. S9) is displayed at 6.02s.(B) Magnified view of
the area in (A) where the lipid-like densities are attached to the complex
(L-a to L-h). The tips of L-c and L-h make contact. L-f is a bulkier density whose
contour resembles a cholesterol group. The visualization threshold was set at
6.02s.(C) Cross section at the level indicated by the gray line in (A). The map
and model are superimposed. Stars (magenta) indicate contacts between L-c
and F607(M3). The details within the dashed rectangle are shown in (E).
(D) Superimposed density map and a molecular model, showing contacts


made between L-f (cholesterol) and side chains of GluA2 and CNIH3. The
tips of L-c and L-h make contact at the arrow. The visualization threshold was
setat5.32s.(E) Molecular architecture ofthe GluA2/CNIH3 interface.
F3, -5, and -8 of CNIH3 (cyan) contact residues in M1 (E524, M527, C528, and
F531) and M4 (L789, A793, and Y797) of adjacent subunits of GluA2. Y797
(M4) and M527 (M1) simultaneously contact lipid-like densities L-f and L-b,
respectively. Y523 (M1), which does not contact CNIH3, is immediately
next to the interface and contacts L-c. Single-letter abbreviations for the
aminoacidresiduesareasfollows:A,Ala;C,Cys;D,Asp;E,Glu;F,Phe;
G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg;
S, Ser; T, Thr; V, Val; W, Trp; and Y, Tyr.

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