eLife
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Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses
eLife - Tập 6
The subunit composition of synaptic NMDA receptors (NMDAR), such as the relative
content of GluN2A- and GluN2B-containing receptors, greatly influences the
glutamate synaptic transmission. Receptor co-agonists, glycine and D-serine,
have intriguingly emerged as potential regulators of the receptor trafficking in
addition to their requirement for its activation. Using a combination of
single-molecu...
Direction-dependent arm kinematics reveal optimal integration of gravity cues
eLife - Tập 5
The brain has evolved an internal model of gravity to cope with life in the
Earth's gravitational environment. How this internal model benefits the
implementation of skilled movement has remained unsolved. One prevailing theory
has assumed that this internal model is used to compensate for gravity's
mechanical effects on the body, such as to maintain invariant motor
trajectories. Alternatively, gr...
Structural insights into the light-driven auto-assembly process of the water-oxidizing Mn4CaO5-cluster in photosystem II
eLife - Tập 6
In plants, algae and cyanobacteria, Photosystem II (PSII) catalyzes the
light-driven splitting of water at a protein-bound Mn4CaO5-cluster, the
water-oxidizing complex (WOC). In the photosynthetic organisms, the light-driven
formation of the WOC from dissolved metal ions is a key process because it is
essential in both initial activation and continuous repair of PSII. Structural
information is req...
Structural mechanisms of phospholipid activation of the human TPC2 channel
eLife - Tập 8
Mammalian two-pore channels (TPCs) regulate the physiological functions of the
endolysosome. Here we present cryo-EM structures of human TPC2 (HsTPC2), a
phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2)-activated, Na+ selective
channel, in the ligand-bound and apo states. The apo structure captures the
closed conformation, while the ligand-bound form features the channel in both
open and closed c...
Regulation of mTORC1 by lysosomal calcium and calmodulin
eLife - Tập 5
Blockade of lysosomal calcium release due to lysosomal lipid accumulation has
been shown to inhibit mTORC1 signaling. However, the mechanism by which
lysosomal calcium regulates mTORC1 has remained undefined. Herein we report that
proper lysosomal calcium release through the calcium channel TRPML1 is required
for mTORC1 activation. TRPML1 depletion inhibits mTORC1 activity, while
overexpression or...
Agonist-specific voltage-dependent gating of lysosomal two-pore Na+ channels
eLife - Tập 8
Mammalian two-pore-channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously- expressed,
PI(3,5)P2-activated, Na+-selective channels in the endosomes and lysosomes that
regulate luminal pH homeostasis, membrane trafficking, and Ebola viral
infection. Whereas the channel activity of TPC1 is strongly dependent on
membrane voltage, TPC2 lacks such voltage dependence despite the presence of the
presumed ‘S4 v...
Selective agonist of TRPML2 reveals direct role in chemokine release from innate immune cells
eLife - Tập 7
Cytokines and chemokines are produced and secreted by a broad range of immune
cells including macrophages. Remarkably, little is known about how these
inflammatory mediators are released from the various immune cells. Here, the
endolysosomal cation channel TRPML2 is shown to play a direct role in chemokine
trafficking and secretion from murine macrophages. To demonstrate acute and
direct involveme...
Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function
eLife - Tập 9
Ion selectivity is a defining feature of a given ion channel and is considered
immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2,
which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al.,
2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A
high-throughput screen identified two structurally distinct TPC2 agonists. One
of t...
Engineering induction of singular neural rosette emergence within hPSC-derived tissues
eLife - Tập 7
Human pluripotent stem cell (hPSC)-derived neural organoids display
unprecedented emergent properties. Yet in contrast to the singular
neuroepithelial tube from which the entire central nervous system (CNS) develops
in vivo, current organoid protocols yield tissues with multiple neuroepithelial
units, a.k.a. neural rosettes, each acting as independent morphogenesis centers
and thereby confounding ...
Analysis of cellular behavior and cytoskeletal dynamics reveal a constriction mechanism driving optic cup morphogenesis
eLife - Tập 5
Contractile actomyosin networks have been shown to power tissue morphogenesis.
Although the basic cellular machinery generating mechanical tension appears
largely conserved, tensions propagate in unique ways within each tissue. Here we
use the vertebrate eye as a paradigm to investigate how tensions are generated
and transmitted during the folding of a neuroepithelial layer. We record
membrane pul...
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