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2016 ; 148
(5
): 375-392
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Independent activation of ion conduction pores in the double-barreled
calcium-activated chloride channel TMEM16A
#MMPMID27799318
Lim NK
; Lam AK
; Dutzler R
J Gen Physiol
2016[Nov]; 148
(5
): 375-392
PMID27799318
show ga
The TMEM16 proteins constitute a family of membrane proteins with unusual
functional breadth, including lipid scramblases and Cl(-) channels. Members of
both these branches are activated by Ca(2+), acting from the intracellular side,
and probably share a common architecture, which was defined in the recent
structure of the lipid scramblase nhTMEM16. The structural features of subunits
and the arrangement of Ca(2+)-binding sites in nhTMEM16 suggest that the dimeric
protein harbors two locations for catalysis that are independent with respect to
both activation and lipid conduction. Here, we ask whether a similar independence
is observed in the Ca(2+)-activated Cl(-) channel TMEM16A. For this purpose, we
generated concatenated constructs containing subunits with distinct activation
and permeation properties. Our biochemical investigations demonstrate the
integrity of concatemers after solubilization and purification. During
investigation by patch-clamp electrophysiology, the functional behavior of
constructs containing either two wild-type (WT) subunits or one WT subunit paired
with a second subunit with compromised activation closely resembles TMEM16A. This
resemblance extends to ion selectivity, conductance, and the concentration and
voltage dependence of channel activation by Ca(2+) Constructs combining subunits
with different potencies for Ca(2+) show a biphasic activation curve that can be
described as a linear combination of the properties of its constituents. The
functional independence is further supported by mutation of a putative
pore-lining residue that changes the conduction properties of the mutated
subunit. Our results strongly suggest that TMEM16A contains two ion conduction
pores that are independently activated by Ca(2+) binding to sites that are
embedded within the transmembrane part of each subunit.
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