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RESEARCH HIGHLIGHTS
Theorem. In contrast to Ih -C60 fullerene,
the D2d -B40 cage is not perfectly smooth
but has eight quasi-planar B6 triangles,
two hexagonal holes and four heptagonal
holes resembling a Chinese red lantern.
The curved heptagons, similar to those in
all-carbon heptafullerenes [6], have been
previously predicted to exist in all-boron
fullerenes to release strain [4].
Discovery of this B40 fullerene is extraordinary because its signals in photoelectron spectra overlapped with those of
another isomer (2D flat B40 ; see Fig. 1c).
Fortunately, the intensity ratio of the first
bands from the 2D planar and 3D spherical structures can be varied depending
on the conditions of supersonic expansion. The remarkable stability of the 3D
B40 fullerene with a sizable gap between
its highest occupied and lowest unoccupied molecular orbital energy levels stem
from its ‘spherical delocalization’ with
all of the 120 valence electrons form-
Rees
ing delocalized bonds (48 σ and 12 π
bonds), as determined by photoelectron
spectroscopy.
As the first all-boron fullerene observed experimentally, the D2d -B40 cluster marks a milestone in boron chemistry.
This elegant work bridges the gap between boron and carbon fullerenes, and
is important for understanding the guiding principles behind the structural and
bonding characteristics of all-boron clusters. Macroscopic synthesis and isolation
of pristine all-boron fullerene could be a
future task for chemists. Despite the challenges of this avenue of research, the B40
cluster may initiate a new direction of
boron chemistry as a potential new inorganic ligand or building block in chemical manipulation. For example, it may be
possible to modify the cage to produce
exohedral derivatives resembling boranes
or encapsulate metal atoms to form metalloborospherenes.
3
Su-Yuan Xie
College of Chemistry and Chemical Engineering,
Xiamen University, China
E-mail: [email protected]
REFERENCES
1. Zhai, HJ, Kiran, B and Li, J et al. Nat Mater 2003;
2: 827–33.
2. Piazza, ZA, Hu, HS and Li, WL et al. Nat Commun
2014; 5: 3113.
3. Yan, QB, Sheng, XL, and Zheng, QR et al. Phys Rev
B 2008; 78: 201401(R).
4. Wang, L, Zhao, JJ and Li, FY et al. Chem Phys Lett
2010; 501: 16–9.
5. Zhai, HJ, Zhao, YF and Li, WL et al. Nat Chem
2014; 6: 727–31.
6. Tan, YZ, Chen, RT and Liao, ZJ et al. Nat Commun
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doi: 10.1093/nsr/nwv004
Advance access publication 23 February 2015
BIOLOGY & BIOCHEMISTRY
Powering brain power: GLUT1 and the era of structure based human
transporter biology
Douglas C. Rees
Every student of biochemistry quickly appreciates the central role of glycolysis
in cellular metabolism. What is not usually addressed in an introductory course
is how glucose gets inside a cell in the
first place. Specialized integral membrane
proteins known as transporters are responsible for glucose uptake; in mammals, glucose is imported by members of
the GLUT family of which 14 different
varieties have been identified in humans
[1]. GLUT transporters are members of
the major facilitator superfamily of transporters and catalyze the facilitated uptake of glucose in the thermodynamically
favored direction. The most widely distributed version is GLUT1 that is responsible for getting glucose into red blood
cells and across the blood brain barrier,
among many other roles [2].
As a relatively abundant membrane
protein (comprising ∼15% of the
membrane proteins in red blood cells),
GLUT1 has been the subject of many
pioneering transport studies, including
the key contribution of Widdas [3]
that glucose transport is mediated by
a carrier that can alternately access the
two sides of the membrane. An essential
role for GLUT1 is keeping brain cells
fueled with glucose; as the brain operates
at ∼20 W [4], this metabolic engine
consumes over 1018 molecules of glucose
per second. To satisfy this demand, the
brain needs a minimum of 1015 GLUT1
transporters operating at their maximal speed (∼103 s−1 ). In view of the
consequences of perturbing the cellular
energy supply, it is not surprising that
mutations in GLUT1 and other GLUT
family members are associated with various diseases, or that cancer cells requiring more glucose have increased levels
of this transporter to fuel their malignant
metabolism.
Given the essential physiological
roles, the recent crystal structure determination of GLUT1 by Nieng Yan and
co-workers [5] represents a landmark
accomplishment, by providing an atomic
resolution foundation to understand the
function of this remarkable protein at the
molecular level. GLUT1 is the first structurally characterized human transporter
of known substrate, and together with
ABCB10 [6], one of only two structurally
characterized human transporters. From
the structure, a mechanistic model for
GLUT1 transport was developed that
provides a framework for understanding
4
RESEARCH HIGHLIGHTS
Natl Sci Rev, 2015, Vol. 2, No. 1
the disease consequences of GLUT1
mutants. Beyond the biological impact,
the structure determination not only
gets high scores for artistic quality but
also represents a significant degree of
technical difficulty; success was not the
result of luck but rather required inspired
experimental design and hard work.
What is next? With the structure of
the inward facing conformation solved,
the next challenge will be to trap and
structurally characterize GLUT1 in other
mechanistically relevant states (outward
facing, occluded) and in the presence of
substrates. Although GLUT1 is a uniporter, the transport kinetics are nontrivial and beg a molecular interpretation [2]. Building on this knowledge,
therapeutics may be developed to regulate the function of GLUT1 in response
to mutation and cancer. Realizing these
long-term goals will require a significant
amount of glucose-fueled brain power,
but the crucial first step has been brilliantly taken by Yan and co-workers.
Douglas C. Rees
Division of Chemistry and Chemical Engineering,
Howard Hughes Medical Institute, California
Institute of Technology, USA
E-mail: [email protected]
2. Carruthers, A, DeZutter, J and Ganguly, A et al.
Am J Physiol-Endocrinol Metab 2009; 297: E836–
48.
3. Widdas, WF. J Physiol-London 1952; 118: 23–39.
4. Clarke, DD and Sokoloff, L. Circulation and energy
metabolism of the brain. In: Siegel, GJ et al. (ed.).
Basic Neurochemistry: Molecular, Cellular and
Medical Aspects, 6th edn. Philadelphia: LippincottRaven Publishers, 1999, 637–69.
5. Deng, D, Xu, C and Sun, PC et al. Nature 2014; 510:
121–5.
6. Shintre, CA, Pike, ACW and Li, Q et al. Proc Natl
Acad Sci USA 2013; 110: 9710–5.
REFERENCES
1. Thorens, B and Mueckler, M. Am J PhysiolEndocrinol Metab 2010; 298: E141–5.
doi: 10.1093/nsr/nwu075
Advance access publication 23 February 2015
BIOLOGY & BIOCHEMISTRY
The cryo-electron microscopy structure of γ -secretase: towards
complex assembly, substrate recognition and a catalytic mechanism
Yanyong Kang1 , Karsten Melcher1 and H. Eric Xu1,2,∗
Alzheimer’s disease (AD) is the most
common form of neurodegenerative disorder to cause dementia in the elderly.
It affects millions of people worldwide
and puts tremendous emotional and economic burden on affected families. It
is estimated that care for AD patients
costs more than $200 billion annually in
the United States [1]. Despite the aging
global population and prevalence and effects of AD, there is no effective treatment. Finding a cure or preventative is
one of the biggest challenges of the 21st
century and represents one of the highest
priorities in life science research and drug
discovery.
A hallmark of AD is the presence
of plaques found between neurons in
the brain. These mainly consist of insoluble β-amyloid protein fragments and
are thought to be cytotoxic when aggregated. This can lead to neuron death
and subsequent loss of memory and
perception. The β-amyloid peptide has
40–42 residues and comes from the
transmembrane (TM) segment of amyloid precursor protein (APP), which has
a large extracellular domain (ECD) and
a small intracellular domain. APP can be
processed by two different pathways. It
can be cleaved by α-secretase to release
the APP ECD. This cleavage blocks production of β-amyloid and reduces plaque
buildup. In the second pathway, APP is
first cleaved by β-secretase at the extracellular side near the TM segment, and
then by γ -secretase within the TM segment. This releases β-amyloid peptides
with lengths of 37–43 residues. The two
major forms of β-amyloid peptides have
40 (Aβ-40) and 42 residues (Aβ-42)
and contain most of the TM segment.
These peptides, especially the longer Aβ42, are hydrophobic and can easily aggregate into large oligomers.
The production of β-amyloid could
be blocked by inhibiting either β- or γ secretase as an effective treatment for
AD. However, over the last decade, there
have been several unsuccessful attempts
at this, including the costly withdrawal
of three late stage clinical trials [2]. Mutations causing a loss of function in γ secretase may also be the cause of AD,
and thus simple inhibition of γ -secretase
would not offer an effective therapeutic solution [3]. In addition, γ -secretase
processes the Notch receptors, which
play an important role to regulate cell biology. As a result, full inhibition of γ secretase could result in toxic side effects.
There is now a need for better understanding of the biochemistry and structure of γ -secretase.
The γ -secretase intramembrane
protease complex has four core subunits:
presenilin, nicastrin (NCT), anterior
pharynx-defective 1 (APH-1) and presenilin enhancer 2 (PEN-2). Presenilin is
a catalytic subunit with a protease active
site containing two aspartyl residues
located in TM helices 6 and 7 (TM6 and
TM7). The accessary functions of TM
proteins APH-1, PEN-2 and NCT are
required for enzyme activity. In addition