103 research outputs found
Differential membrane binding of α/β-peptide foldamers: implications for cellular delivery and mitochondrial targeting
The intrinsic pathway of apoptosis is regulated by the Bcl-2 family of proteins. Inhibition of the anti-apoptotic members represents a strategy to induce apoptotic cell death in cancer cells. We have measured the membrane binding properties of a series of peptides, including modified α/β-peptides, designed to exhibit enhanced membrane permeability to allow cell entry and improved access for engagement of Bcl-2 family members. The peptide cargo is based on the pro-apoptotic protein Bim, which interacts with all anti-apoptotic proteins to initiate apoptosis. The α/β-peptides contained cyclic β-amino acid residues designed to increase their stability and membrane-permeability. Dual polarisation interferometry was used to study the binding of each peptide to two different model membrane systems designed to mimic either the plasma membrane or the outer mitochondrial membrane. The impact of each peptide on the model membrane structure was also investigated, and the results demonstrated that the modified peptides had increased affinity for the mitochondrial membrane and significantly altered the structure of the bilayer. The results also showed that the presence of an RRR motif significantly enhanced the ability of the peptides to bind to and insert into the mitochondrial membrane mimic, and provide insights into the role of selective membrane targeting of peptides
Noncommutative Dipole Field Theories And Unitarity
We extend the argument of Gomis and Mehen for violation of unitarity in field
theories with space-time noncommutativity to dipole field theories. In dipole
field theories with a timelike dipole vector, we present 1-loop amplitudes that
violate the optical theorem. A quantum mechanical system with nonlocal
potential of finite extent in time also shows violation of unitarity.Comment: typos corrected, more details added in Sec 5, version to appear in
JHE
A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation
Like Bcl-2, Mcl-1 is an important survival factor for many cancers, its expression contributing to chemoresistance and disease relapse. However, unlike other prosurvival Bcl-2–like proteins, Mcl-1 stability is acutely regulated. For example, the Bcl-2 homology 3 (BH3)–only protein Noxa, which preferentially binds to Mcl-1, also targets it for proteasomal degradation. In this paper, we describe the discovery and characterization of a novel BH3-like ligand derived from Bim, BimS2A, which is highly selective for Mcl-1. Unlike Noxa, BimS2A is unable to trigger Mcl-1 degradation, yet, like Noxa, BimS2A promotes cell killing only when Bcl-xL is absent or neutralized. Furthermore, killing by endogenous Bim is not associated with Mcl-1 degradation. Thus, functional inactivation of Mcl-1 does not always require its elimination. Rather, it can be efficiently antagonized by a BH3-like ligand tightly engaging its binding groove, which is confirmed here with a structural study. Our data have important implications for the discovery of compounds that might kill cells whose survival depends on Mcl-1
Trans-Pacific Transport of Saharan Dust to Western North America: A Case Study
The first documented case of long range transport of Saharan dust over a pathway spanning Asia and the Pacific to Western North America is described. Crustal material generated by North African dust storms during the period 28 February - 3 March 2005 reached western Canada on 13-14 March 2005 and was observed by lidar and sunphotometer in the Vancouver region and by high altitude aerosol instrumentation at Whistler Peak. Global chemical models (GEOS-CHEM and NRL NAAPS) confirm the transport pathway and suggest source attribution was simplified in this case by the distinct, and somewhat unusual, lack of dust activity over Eurasia (Gobi and Takla Makan deserts) at this time. Over western North America, the dust layer, although subsiding close to the boundary layer, did not appear to contribute to boundary layer particulate matter concentrations. Furthermore, sunphotometer observations (and associated inversion products) suggest that the dust layer had only subtle optical impact (Aerosol Optical Thickness (Tau(sub a500)) and Angstrom exponent (Alpha(sub 440-870) were 0.1 and 1.2 respectively) and was dominated by fine particulate matter (modes in aerodynamic diameter at 0.3 and 2.5microns). High Altitude observations at Whistler BC, confirm the crustal origin of the layer (rich in Ca(++) ions) and the bi-modal size distribution. Although a weak event compared to the Asian Trans-Pacific dust events of 1998 and 2001, this novel case highlights the possibility that Saharan sources may contribute episodically to the aerosol burden in western North America
Bax Crystal Structures Reveal How BH3 Domains Activate Bax and Nucleate Its Oligomerization to Induce Apoptosis
SummaryIn stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to mediate this pivotal, poorly understood step. To clarify the conformational changes that induce Bax oligomerization, we determined crystal structures of BaxΔC21 treated with detergents and BH3 peptides. The peptides bound the Bax canonical surface groove but, unlike their complexes with prosurvival relatives, dissociated Bax into two domains. The structures define the sequence signature of activator BH3 domains and reveal how they can activate Bax via its groove by favoring release of its BH3 domain. Furthermore, Bax helices α2–α5 alone adopted a symmetric homodimer structure, supporting the proposal that two Bax molecules insert their BH3 domain into each other’s surface groove to nucleate oligomerization. A planar lipophilic surface on this homodimer may engage the membrane. Our results thus define critical Bax transitions toward apoptosis
The intracellular chloride ion channel protein CLIC1 undergoes a redox-controlled structural transition.
Most proteins adopt a well defined three-dimensional structure; however, it is increasingly recognized that some proteins can exist with at least two stable conformations. Recently, a class of intracellular chloride ion channel proteins (CLICs) has been shown to exist in both soluble and integral membrane forms. The structure of the soluble form of CLIC1 is typical of a soluble glutathione S-transferase superfamily protein but contains a glutaredoxin-like active site. In this study we show that on oxidation CLIC1 undergoes a reversible transition from a monomeric to a non-covalent dimeric state due to the formation of an intramolecular disulfide bond (Cys-24-Cys-59). We have determined the crystal structure of this oxidized state and show that a major structural transition has occurred, exposing a large hydrophobic surface, which forms the dimer interface. The oxidized CLIC1 dimer maintains its ability to form chloride ion channels in artificial bilayers and vesicles, whereas a reducing environment prevents the formation of ion channels by CLIC1. Mutational studies show that both Cys-24 and Cys-59 are required for channel activity
Enhancons, Fuzzy Spheres and Multi-Monopoles
We study the `enhancon', a spherical hypersurface apparently made of
D-branes, which arises in string theory studies of large N SU(N) pure gauge
theories with eight supercharges. When the gauge theory is 2+1 dimensional, the
enhancon is an S^2. A relation to charge N BPS multi-monopoles is exploited to
uncover many of its detailed properties. It is simply a spherical slice through
an Atiyah-Hitchin-like submanifold of the charge BPS monopole moduli space.
In the form of Nahm data, it is built from the N dimensional irreducible
representation of SU(2). In this sense the enhancon is a non-commutative
sphere, reminiscent of the spherical `dielectric' branes of Myers.Comment: 25 pages, latex, 3 primary figures, psfig (v2: Omission of references
to important early work on multi-monopoles is fixed. Note added on possible
relations to certain other recent work on large N, monopoles, and
non-commutativity. A few typos fixed.) (v3: Extensive revision. Statements
about role of Atiyah-Hitchin manifold and instanton corrections refined.
Speculation about location of Higgs zeros removed. Discussion improved in
many places.
M(atrix) Theory: Matrix Quantum Mechanics as a Fundamental Theory
A self-contained review is given of the matrix model of M-theory. The
introductory part of the review is intended to be accessible to the general
reader. M-theory is an eleven-dimensional quantum theory of gravity which is
believed to underlie all superstring theories. This is the only candidate at
present for a theory of fundamental physics which reconciles gravity and
quantum field theory in a potentially realistic fashion. Evidence for the
existence of M-theory is still only circumstantial---no complete
background-independent formulation of the theory yet exists. Matrix theory was
first developed as a regularized theory of a supersymmetric quantum membrane.
More recently, the theory appeared in a different guise as the discrete
light-cone quantization of M-theory in flat space. These two approaches to
matrix theory are described in detail and compared. It is shown that matrix
theory is a well-defined quantum theory which reduces to a supersymmetric
theory of gravity at low energies. Although the fundamental degrees of freedom
of matrix theory are essentially pointlike, it is shown that higher-dimensional
fluctuating objects (branes) arise through the nonabelian structure of the
matrix degrees of freedom. The problem of formulating matrix theory in a
general space-time background is discussed, and the connections between matrix
theory and other related models are reviewed.Comment: 56 pages, 3 figures, LaTeX, revtex style; v2: references adde
USp(2k) Matrix Model: Nonperturbative Approach to Orientifolds
We discuss theoretical implications of the large k USp(2k) matrix model in
zero dimension. The model appears as the matrix model of type IIB superstrings
on a large orientifold via the matrix twist operation. In the
small volume limit, the model behaves four dimensional and its T dual is
six-dimensional worldvolume theory of type I superstrings in ten spacetime
dimensions. Several theoretical considerations including the analysis on planar
diagrams, the commutativity of the projectors with supersymmetries and the
cancellation of gauge anomalies are given, providing us with the rationales for
the choice of the Lie algebra and the field content. A few classical solutions
are constructed which correspond to Dirichlet p-branes and some fluctuations
are evaluated. The particular scaling limit with matrix T duality
transformation is discussed which derives the F theory compactification on an
elliptic fibered K3.Comment: LaTeX, 29 pages, 3 figures. PostScript problems are fixe
Teleparallel Gravity and Dimensional Reductions of Noncommutative Gauge Theory
We study dimensional reductions of noncommutative electrodynamics on flat
space which lead to gauge theories of gravitation. For a general class of such
reductions, we show that the noncommutative gauge fields naturally yield a
Weitzenbock geometry on spacetime and that the induced diffeomorphism invariant
field theory can be made equivalent to a teleparallel formulation of gravity
which macroscopically describes general relativity. The Planck length is
determined in this setting by the Yang-Mills coupling constant and the
noncommutativity scale. The effective field theory can also contain
higher-curvature and non-local terms which are characteristic of string theory.
Some applications to D-brane dynamics and generalizations to include the
coupling of ordinary Yang-Mills theory to gravity are also described.Comment: 31 pages LaTeX; References adde
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