Conformational
Coupling and trans-Inhibition in the
Human Antigen Transporter Ortholog TmrAB Resolved with Dipolar EPR
Spectroscopy
Version 3 2018-03-23, 18:39
Version 2 2018-02-01, 19:48
Version 1 2018-01-30, 18:52
Posted on 2018-03-23 - 18:39
ATP-binding cassette (ABC) exporters
actively move chemically diverse
substrates across biological membranes. Their malfunction leads to
human diseases. Many ABC exporters encompass asymmetric nucleotide-binding
sites (NBSs), and some of them are inhibited by the transported substrate.
The functional relevance of the catalytic asymmetry or the mechanism
for trans-inhibition remains elusive. Here, we investigated TmrAB,
a functional homologue of the human antigen translocation complex
TAP using advanced electron–electron double resonance spectroscopy.
In the presence of ATP, the heterodimeric ABC exporter exists in a
tunable equilibrium between inward- and outward-facing conformations.
The two NBSs exhibit pronounced asymmetry in the open-to-close equilibrium.
The closed conformation is more favored at the degenerate NBS, and
closure of either of the NBS is sufficient to open the extracellular
gate. We define the mechanistic basis for trans-inhibition, which
operates by a reverse transition from the outward-facing state through
an occluded conformation. These novel findings uncover the central
role of reversible conformational equilibrium in the function and
regulation of an ABC exporter and establish a mechanistic framework
for future investigations on other medically important transporters
with imprinted asymmetry. Also, this study demonstrates for the first-time
the feasibility to resolve equilibrium populations at multiple domains
and their interdependence for global conformational changes in a large
membrane protein complex.
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Barth, Katja; Hank, Susanne; Spindler, Philipp E.; Prisner, Thomas F.; Tampé, Robert; Joseph, Benesh (2018). Conformational
Coupling and trans-Inhibition in the
Human Antigen Transporter Ortholog TmrAB Resolved with Dipolar EPR
Spectroscopy. ACS Publications. Collection. https://doi.org/10.1021/jacs.7b12409
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AUTHORS (6)
KB
Katja Barth
SH
Susanne Hank
PS
Philipp E. Spindler
TP
Thomas F. Prisner
RT
Robert Tampé
BJ
Benesh Joseph
KEYWORDS
TAPheterodimeric ABC exporterMany ABC exportersextracellular gatesubstratetrans-inhibitionfuture investigationsHuman Antigen Transporter Ortholog TmrABABC exporterNBSs exhibitoutward-facing conformationsasymmetrymembrane proteinresonance spectroscopynovel findingstunable equilibriumDipolar EPR Spectroscopy ATP-binding cassetteantigen translocationopen-to-close equilibriumnucleotide-binding sitesequilibrium populationsoutward-facing state