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lengths of 38 to 50 mm), which arrived in the
North Pacific when the Bering Strait first
opened 5.3 to 5.4 million years ago (8), these
species do not exceed 30 mm in maximum
shell dimension and might be unable to
establish populations in the Bering Sea,
where competition and predation are intense.
Geographic expansions within and between oceans are generally concentrated during warm periods even in areas far from the
poles. The coming warmth may therefore initiate an age of renewed interoceanic dispersal
worldwide, a natural experiment that we
should all anticipate with great interest.
References and Notes
3.
4.
5.
6.
7.
8.
9.
Biology, and Geology, W. O. Smith Jr., Ed. (Academic
Press, San Diego, 1990), pp. 631–685.
A. A. Krylov et al., Paleoceanography 23, PA1S06,
10.1029/2007PA001497 (2008).
L. D. Carter, J. Brigham-Grette, L. Marincovich Jr.,
V. L. Pease, J. W. Hillhouse, Geology 14, 675
(1986).
O. G. N. Andersen, in The Arctic Seas: Climatology,
Oceanography, Geology, and Biology, Y. Herman, Ed.
(Nostrand Reinhold, New York, 1989), pp. 147–191.
J. Stroeve, M. M. Holland, W. Meier, T. Scambos, M.
Terreze, Geophys. Res. Lett. 34, L09501 (2007).
The values in this paragraph are from a literature
synthesis, partly based on (1) but with updates.
A. Yu. Gladenkov, A. E. Oleinik, L. Marincovich Jr.,
K. B. Barinov, Palaeogeogr. Palaeoecol. Palaeoclimatol.
183, 321 (2002).
R. Stöckli, E. Vermote, N. Saleous, R. Simmon,
D. Herring, Eos 87, 49 (2006).
1. G. J. Vermeij, Paleobiology 17, 281 (1991).
2. P. K. Dayton, in Polar Oceanography B: Chemistry,
10.1126/science.1160852
Downloaded from www.sciencemag.org on August 7, 2008
Climate models and recently observed
trends toward contraction and thinning of
Arctic sea ice predict seasonally or perennially ice-free conditions in the nearshore
Arctic Ocean by 2050 or even earlier (6),
reestablishing a regime of temperature and
productivity similar to that of the midPliocene. Marine mollusks, whose past and
present distributions are well documented,
offer unparalleled insight into how marine
species and communities are likely to
respond to these future conditions.
At least 77 molluscan lineages (35% of
219 shell-bearing, shallow-water mollusk
species in the northern Bering Sea) have the
potential to extend to the North Atlantic via
the warmer Arctic Ocean without direct
human assistance (7). Of these, 19 have
Atlantic members but are separated from
them by wide geographic and genetic gaps; 2
have extinct but no living North Atlantic representatives; and 56 have not yet extended
beyond the Bering Sea or the Chukchi Sea
just north of Bering Strait (see the figure).
The remaining 142 Bering Sea lineages are
distributed throughout the Arctic and subpolar North Atlantic Oceans. The number of
would-be interoceanic invaders could well
be much higher, because many species with
northern limits in Kamchatka and the
Aleutian-Commander island arc can expand
northward and therefore also become candidates for trans-Arctic invasion.
Pacific-derived species already have the
largest body sizes in all ecological guilds in
the Arctic and in many on the east and west
sides of the North Atlantic, including mussels, barnacles, coiled grazing snails, and
predatory whelks. The Bering Sea source
pool contains many additional large-bodied
species that may establish viable populations in the temperate North Atlantic. Given
that marine invasions rarely lead to extinctions in recipient ecosystems, these transArctic invaders of the future will likely
enrich Atlantic biotas both by adding new
lineages and by hybridizing with established
species. Competitive standards in the North
Atlantic will rise because of the addition of
large-bodied, fast-growing species to which
natives must adapt.
As in the past, few Atlantic to Pacific
invasions are expected. Most of the 50 shallow-water, Atlantic-derived Arctic mollusks
(out of about 180 species in the American
Arctic) are small-bodied compared to both
the Pacific-derived members of the Arctic
fauna and to potential Pacific invaders in the
Bering Sea. With the exception of the largest
Atlantic-derived species (bivalves in the
genera Tridonta and Cyrtodaria, with shell
STRUCTURAL BIOLOGY
Symmetric Transporters for
Asymmetric Transport
Nathan K. Karpowich and Da-Neng Wang
The crystal structure of a membrane transporter protein sheds light on the molecular mechanism
by which glucose is absorbed by the intestine and the kidneys.
he average Western adult metabolizes
hundreds of grams of carbohydrates
per day, half of which is used as an
energy source for the brain. To benefit from
these ingested carbohydrates, they must first
be broken down into simple sugars, such as
glucose, and absorbed through the epithelial
cells of the intestine. The glucose must then
be reabsorbed in the kidneys. On page 810
of this issue, Faham et al. (1) report a major
advance in elucidating the molecular mechanism by which this highly effective absorption is realized.
Glucose is absorbed from the lumen into
the epithelial cell by the Na+/glucose cotransporter SGLT1 in the intestine and by
the related SGLT2 in the kidney (see the
figure). The glucose is then exported by the
glucose transporter GLUT2 to the basal
side of the cell into the blood. These transport proteins share the same substrate and
all function as so-called secondary membrane transporters, but they are members
of distinct protein families: SGLT1 and
SGLT2 are solute sodium symporters (SSS),
T
Kimmel Center for Biology and Medicine at the Skirball
Institute of Biomolecular Medicine, and Department of Cell
Biology, New York University School of Medicine, 540 First
Avenue, New York, NY 10016, USA. E-mail: karpowic@
saturn.med.nyu.edu; [email protected]
www.sciencemag.org
SCIENCE
VOL 321
Published by AAAS
whereas GLUT2 is a member of the major
facilitator superfamily (MFS). Faham et al.
now report the structure of a bacterial
SSS protein.
Secondary membrane transporters couple “uphill” translocation of substrate across
the membrane to the energetically favorable
flow of ions down their concentration gradient. Both the substrates they transport, ranging from ions and sugars to lipophilic drugs,
and their protein architectures are diverse:
More than 200 distinct families can be classified on the basis of primary structure.
Nevertheless, biochemical, kinetic, and
structural studies suggest that all secondary
membrane transporters operate via a common alternating-access mechanism (2).
In this mechanism, the transporter is
believed to have two major alternating conformations, inward-facing (Ci) and outwardfacing (Co). Interconversion between the
two conformations facilitates substrate
translocation across the membrane. This
kinetic scheme can be realized through two
types of conformational changes: a rockerswitch movement of the two halves of the
protein (3) and an alternating gate or gatedpore mode (4)—that is, a channel-like protein with two gates that open alternatively
(see the figure). MFS proteins are thought to
8 AUGUST 2008
781
Glucose
operate via the rocker-switch mode,
and two MFS members have been
Apical surface
Na+
Glucose
visualized in their Ci conformation
SGLT1
at high-resolution by x-ray crystallography (5, 6). Structures of several other transporter proteins presumed to operate via the gated-pore
mode have also been determined
(7–9), but none of these structures
are of proteins from the same transporter family. Hence, it remains
unclear whether any transporter works
CYTOPLASM
as a gated pore.
Faham et al. now report the structure of vSGLT—an SSS protein
from Vibrio parahaemolyticus that
shares 30% sequence identity with
human SGLT1 (1). The core of the
Basal surface GLUT2
protein is made of two inverted, symmetric halves. The substrate (galactose along with a Na+ ion) is bound at Gated pores and rocker switches. Net sugar transport across
the center of the core helices in the the intestinal epithelia is catalyzed by SGLT1 in the apical memmiddle of the membrane. The sub- brane, which couples Na+ influx down its concentration gradistrate is closed off to the extramem- ent to glucose uptake, and by GLUT2, which facilitates glucose
brane space by a thick gate made of transport across the membrane to the basal side of the cell. A
similar transport pathway is responsible for glucose reabsorphydrophobic residues. The cytoplastion in the kidneys. Faham et al. show that in gated pores such
mic gate is much thinner, consisting as SGLT1, the rotation of two broken helices permits alternating
of only a few side chains, and a large access of the substrates to the opposing sides of the membrane.
cavity is found outside this gate. Rocker switches are thought to function by the rotation of two
Therefore, the structure presents the domains toward one another, alternately exposing the subsubstrate-bound, Ci conformation of strate-binding site to each side of the membrane.
the protein.
The vSGLT structure resembles
depressants inhibit leucine transport by direct
that of LeuT, a bacterial member of the neu- competition at this site (13–15).
rotransmitter sodium symporter (NSS) famBoth SSS-type gated pores and MFSily (9). The core helices of vSGLT share only type rocker switches are composed of two
11% sequence identity with LeuT, but the symmetry-related homologous domains, but
two transporter families may nevertheless their interdomain association is distinct.
share a common ancestor (10, 11). The LeuT Gated pores like SGLT are formed by the
crystal structure is in its substrate-bound, Co association of two V-shaped domains interconformation (9), whereas the vSGLT struc- twined in an antiparallel manner. The subture is in the Ci conformation (1). Faham et strate-binding site is located in the center of
al. mapped the vSGLT sequence onto the the membrane at two broken helices, one
LeuT structure and generated a Co model for from each domain. The vSGLT structure
vSGLT. Comparison of the two conforma- shows that alternating access is achieved by
tions allowed the authors to propose a rea- rotating the cytoplasmic portion of two brosonable model for the Na+-coupled galac- ken helices from the substrate-binding site.
tose transport across the membrane by In contrast, in MFS, two parallel helical bunvSGLT. Such internal symmetry has recently dles associate to form a shared binding site
also been used to model the Ci conformation at their interface. Substrate binding at this
of LeuT (12).
interface from one side of the membrane
On the cytoplasmic side, the vSGLT Ci drives domain closure, thereby alternately
structure lacks a vestibule found between the exposing the binding site to opposite sides
gate and the tip of a hairpin loop on the sym- of the bilayer.
metric, extracellular side of the LeuT Co strucThe gated-pore and rocker-switch modes
ture (9). This vestibule might function as a both use electrochemical gradient-driven
reservoir for concentrating the substrate from membrane transport. However, because the
the extracellular space for substrate import. conformational changes required for transRecent work on LeuT has shown that the sub- port in a gated pore are typically smaller
strate, leucine, binds to a low-affinity second- than in a rocker-switch transporter, the less
ary site in the vestibule and that tricyclic anti- dynamic nature of gated pores may offer a
782
8 AUGUST 2008
VOL 321
SCIENCE
Published by AAAS
potential advantage in crystallization experiments. The differences do not stop here. A
gated pore resembles an ion channel with
two gates instead of one and can often display uncoupled, channel-like ion conduction. Such uncoupled current has been
observed in several NSS proteins (16).
Likewise, in the absence of glucose, SGLT1
displays channel-like behaviors (17). In contrast, the single thick gate of rocker switches
prevents diffusion of ions across the membrane, and MFS proteins do not display a
leak current.
The vSGLT structure provides an important piece of the puzzle in understanding the
molecular mechanism of sugar absorption
in the human body. To completely understand this physiological process, however,
there is an urgent need to identify and better
characterize all conformational states in the
transport cycle for a particular protein.
Isolation of secondary transporters in specific conformational states remains a major
technical obstacle for structural studies.
However, with structural information for
some conformational states in hand, spectroscopic techniques can provide precise
information about the nature and magnitude
of the conformational states during the
transport cycle. Now with both conformational states of a gated pore visualized, the
field anxiously awaits the determination of
a rocker-switch structure in its outward-facing conformation.
References and Notes
1.
2.
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9.
10.
11.
12.
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18.
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A. Yamashita, S. K. Singh, T. Kawate, Y. Jin, E. Gouaux,
Nature 437, 215 (2005).
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L. Shi, M. Quick, Y. Zhao, H. Weinstein, J. A. Javitch, Mol.
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D. D. Loo et al., J. Physiol 518, 195 (1999).
N.K.K. is a recipient of an American Heart Association
Postdoctoral Fellowship and of a Ruth L. Kirschstein
National Research Service Award from NIH. The authors’
work was financially supported by the NIH (DK053973,
GM075936, GM075026, and MH083840).
www.sciencemag.org
10.1126/science.1161495
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PERSPECTIVES