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Title
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Structure of the cytosolic portion of the motor protein prestin and functional role of the STAS domain in SLC26/SulP anion transporters.
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Authors
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E.Pasqualetto,
R.Aiello,
L.Gesiot,
G.Bonetto,
M.Bellanda,
R.Battistutta.
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Ref.
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J Mol Biol, 2010,
400,
448-462.
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PubMed id
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Abstract
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Prestin is the motor protein responsible for the somatic electromotility of
cochlear outer hair cells and is essential for normal hearing sensitivity and
frequency selectivity of mammals. Prestin is a member of mammalian solute-linked
carrier 26 (SLC26) anion exchangers, a family of membrane proteins capable of
transporting a wide variety of monovalent and divalent anions. SLC26
transporters play important roles in normal human physiology in different
tissues, and many of them are involved in genetic diseases. SLC26 and related
SulP transporters carry a hydrophobic membrane core and a C-terminal cytosolic
portion that is essential in plasma membrane targeting and protein function.
This C-terminal portion is mainly composed of a STAS (sulfate transporters and
anti-sigma factor antagonist) domain, whose name is due to a remote but
significant sequence similarity with bacterial ASA (anti-sigma factor
antagonist) proteins. Here we present the crystal structure at 1.57 A resolution
of the cytosolic portion of prestin, the first structure of a SulP transporter
STAS domain, and its characterization in solution by heteronuclear
multidimensional NMR spectroscopy. Prestin STAS significantly deviates from the
related bacterial ASA proteins, especially in the N-terminal region,
which-although previously considered merely as a generic linker between the
domain and the last transmembrane helix-is indeed fully part of the domain.
Hence, unexpectedly, our data reveal that the STAS domain starts immediately
after the last transmembrane segment and lies beneath the lipid bilayer. A
structure-function analysis suggests that this model can be a general template
for most SLC26 and SulP anion transporters and supports the notion that STAS
domains are involved in functionally important intramolecular and intermolecular
interactions. Mapping of disease-associated or functionally harmful mutations on
STAS structure indicates that they can be divided into two categories: those
causing significant misfolding of the domain and those altering its interaction
properties.
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