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| Open AccessThe allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling
Class A seven transmembrane helical receptors harbour vestibules at the entrance to the ligand-binding domain. Here, Bocket al. use probes to monitor the conformation of the M2 muscarinic receptor and show that the vestibule alters the extent of receptor movement.
- Andreas Bock
- , Nicole Merten
- & Klaus Mohr
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Article |
Imaging enzyme-triggered self-assembly of small molecules inside live cells
Supramolecular interactions allow some small molecules to self-assemble into nanofibres and hydrogels in aqueous environments. Gaoet al.report a hydrogelator that forms fluorescent nanofibres within cells, leading to the visualization of their self-assembly at the endoplasmic reticulum.
- Yuan Gao
- , Junfeng Shi
- & Bing Xu
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Article |
Rotational dynamics of cargos at pauses during axonal transport
Vesicle trafficking in the cell is likely to involve a tug-of-war between motor proteins of opposing directionality. Guet al. use high-speed single-particle tracking in neurons to uncover rotation of paused cargo vesicles, providing insight into the changing forces as the vesicles change direction.
- Yan Gu
- , Wei Sun
- & Ning Fang
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Article
| Open AccessControlled rotation of the F1-ATPase reveals differential and continuous binding changes for ATP synthesis
Reverse rotation of the F1-ATPase results in the synthesis, rather than hydrolysis of ATP. Adachiet al. show that the molecular mechanism of ATP synthesis is the reverse of hydrolysis-driven rotation of the motor, and that ADP and ATP are discriminated by angle-dependent binding.
- Kengo Adachi
- , Kazuhiro Oiwa
- & Kazuhiko Kinosita Jr
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Article
| Open AccessDistant residues mediate picomolar binding affinity of a protein cofactor
Flavodoxin requires tight binding of its FMN cofactor to be active, but the residues involved are unknown. In this biophysical study, FMN binding is shown to change from nanomolar to picomolar affinity on extremely slow protein relaxation and the residues responsible for cofactor binding are identified.
- Yves J.M. Bollen
- , Adrie H. Westphal
- & Carlo P.M. van Mierlo
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Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers
Glycoprotein hormone receptors show negative cooperativity following a single molecule of agonist binding to each receptor dimer. Here, constitutively active receptors are shown to display less cooperative allosteric regulation, suggesting a direct relationship between conformational changes in the transmembrane domain and allosteric behaviour of the receptor dimers.
- Maxime Zoenen
- , Eneko Urizar
- & Sabine Costagliola
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TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export
The TREX complex and Nxf1 are involved in the export of mRNA from the nucleus but the precise molecular function of TREX is unclear. Here, the TREX components Aly and Thoc5 are shown to bind to Nxf1 resulting in a change in Nxf1 conformation that permits binding to mRNA and nuclear export.
- Nicolas Viphakone
- , Guillaume M. Hautbergue
- & Stuart A. Wilson
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Mechanism of resilin elasticity
Resilin is a polymeric elastic protein that is important for the flight and jumping of insects. Here, the structure-function relationships ofDrosophilaresilin are investigated, and a mechanical model is proposed to account for its elasticity.
- Guokui Qin
- , Xiao Hu
- & David L. Kaplan
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Article
| Open AccessDistinct loops in arrestin differentially regulate ligand binding within the GPCR opsin
Following retinalcis/trans isomerisation, the active form of the G-protein-coupled receptor rhodopsin decays to opsin and all-trans-retinal. In this study, arrestin, a regulator of G-protein-coupled receptor activity, is shown to facilitate the concurrent sequestering of toxic all-trans-retinal and regeneration of 11-cis-retinal within the opsin population.
- Martha E. Sommer
- , Klaus Peter Hofmann
- & Martin Heck
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Article
| Open AccessSwitching of myosin-V motion between the lever-arm swing and Brownian search-and-catch
The motor protein myosin-V transports cargo along actin filaments, but the biophysical mechanisms by which myosin-V generates force are unclear. Here, optical tweezers and a DNA handle are used to study the forces generated by myosin-V: the mechanism of force generation is found to depend on the load applied.
- Keisuke Fujita
- , Mitsuhiro Iwaki
- & Toshio Yanagida
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Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation
Chromatin in embryonic stem cells is present in an open state presumably to facilitate gene expression changes required for pluripotency and subsequent multilineage differentiation. This study describes roles for lamin A, histone acetylation and G9a-mediated histone H3 lysine 9 methylation in regulating chromatin plasticity in these cells.
- Shai Melcer
- , Hadas Hezroni
- & Eran Meshorer
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Crystal structure of a plectonemic RNA supercoil
Nucleic acid superstructures are required to package genomes into the nucleus of cells. In this study, the superstructure of an RNA supercoil species is reported and is shown to be dependent on an RNA-binding protein that induces a higher level of organization compared with DNA superstructures.
- Jason R. Stagno
- , Buyong Ma
- & Xinhua Ji
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Prediction of variable translation rate effects on cotranslational protein folding
Proteins can undergo folding while being translated by the ribosome, and the extent of this folding is influenced by the rate at which amino acids are added to the nascent chain. This study provides a framework for predicting domain folding probabilities as a function of the kinetics of amino-acid addition.
- Edward P. O'Brien
- , Michele Vendruscolo
- & Christopher M. Dobson
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Assembly kinetics determine the architecture of α-actinin crosslinked F-actin networks
Processes that regulate the mechanical and dynamic properties of actin cytoskeleton are important for multiple eukaryotic cell functions. In this study, using reconstituted crosslinked actin networks, organization is found to be determined by the competing kinetics of actin gelation and bundle formation.
- Tobias T. Falzone
- , Martin Lenz
- & Margaret L. Gardel
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Dynamic force-induced direct dissociation of protein complexes in a nuclear body in living cells
Cells can sense their local environment by a process termed mechanotransduction, but whether these signals are relayed to the nucleus is unclear. This study demonstrates that a force applied at the cell surface can alter the localization of proteins within Cajal bodies that are found in the nuclear compartment.
- Yeh-Chuin Poh
- , Sergey P. Shevtsov
- & Ning Wang
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Nanodomain Ca2+ of Ca2+ channels detected by a tethered genetically encoded Ca2+ sensor
Calcium nanodomains arise from the cytoplasmic mouth of calcium channels but have not been directly visualized. In this study, the nanodomain of the CaV2.2 calcium channel is imaged using total internal reflection fluorescence microscopy and a genetically encoded calcium sensor attached to the carboxy terminus.
- Lai Hock Tay
- , Ivy E. Dick
- & David T. Yue
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Perturbation of sodium channel structure by an inherited Long QT Syndrome mutation
Perturbation of the cardiac voltage-gated sodium channel, NaV1.5, by drugs or inherited mutation can underlie and trigger cardiac arrhythmias. Here, the role of the NaV1.5 carboxy terminus in channel inactivation is investigated, and structural details of an arrhythmia associated H6 mutant are reported.
- Ian W. Glaaser
- , Jeremiah D. Osteen
- & Robert S. Kass
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Article
| Open AccessThe dynamic stator stalk of rotary ATPases
The peripheral stalks of rotary ATPases counteract torque generated by rotation of the central stalk during ATP synthesis or hydrolysis. Stewartet al.report the crystal structure of an A-type ATPase/synthase peripheral stalk and identify bending and twisting motions that permit the radial wobbling of the headgroup.
- Alastair G. Stewart
- , Lawrence K. Lee
- & Daniela Stock
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Article
| Open AccessThe dynamic relationships between the three events that release individual Na+ ions from the Na+/K+-ATPase
The Na+/K+-ATPase pump exports three Na+ ions for the exchange of two K+ ions, and three transient current components have been associated with Na+ binding and release. Now, these three components are found to be tightly correlated confirming that the binding and release of Na+ions is sequential.
- David C. Gadsby
- , Francisco Bezanilla
- & Miguel Holmgren
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Article
| Open AccessELL facilitates RNA polymerase II pause site entry and release
The super elongation complex, which is involved in transcriptional elongation, contains the Eleven-nineteen Lysine-rich Leukemia protein (ELL). In this study, ELL is shown to stabilize RNA polymerase II prior to recruitment into the super elongation complex, suggesting ELL has a role in early transcription elongation.
- Jung S. Byun
- , Temesgen D. Fufa
- & Kevin Gardner
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Structural rearrangements underlying ligand-gating in Kir channels
Inward rectifier potassium channels are regulated by a range of ligands that act on a common gate, but the structural details of gating are unclear. Here, the molecular motions associated with gating of KirBac1.1 channels are assessed using small molecule fluorescent probes attached to introduced cysteines.
- Shizhen Wang
- , Sun-Joo Lee
- & Colin G. Nichols
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Super-resolution surface mapping using the trajectories of molecular probes
Surface characterization of soft materialsin situis challenging due to the importance of non-covalent interactions. Now, a new chemical imaging method is reported that generates images of surface interactions by combining many molecular probe trajectories.
- Robert Walder
- , Nathaniel Nelson
- & Daniel K. Schwartz
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Review Article |
Integrating the biophysical and molecular mechanisms of auditory hair cell mechanotransduction
Hair cells of the inner ear transduce vibrations of the basilar membrane into electrical signals by a process known as mechanotransduction. Recent advances in genetic and molecular tools have led to an improved understanding of mechanotransduction as Peng and colleagues summarize in this Review.
- Anthony W. Peng
- , Felipe T. Salles
- & Anthony J. Ricci
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NMDA receptor activation requires remodelling of intersubunit contacts within ligand-binding heterodimers
In non-NMDA glutamate receptors, intersubunit contacts within agonist binding domains affect functional desensitization. Now, NMDA receptor activation, but not desensitization, is shown to involve rearrangements at the heterodimer interface, suggesting that the intersubunit contacts of NMDA and non-NMDA receptors may have distinct functional roles.
- William F. Borschel
- , Swetha E. Murthy
- & Gabriela K. Popescu
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Single-molecule fluorescence spectroscopy maps the folding landscape of a large protein
The folding of multidomain proteins can involve metastable intermediate states. Here, a single-molecule FRET based method is developed and used to identify six metastable states in the folding landscape of the three-domain protein adenylate kinase.
- Menahem Pirchi
- , Guy Ziv
- & Gilad Haran
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Review Article |
Capturing the essence of folding and functions of biomolecules using coarse-grained models
Coarse-grained models can be used to study the folding of biological macromolecules such as DNA, RNA and proteins. In this Review, Hyeon and Thirumalai describe recent advances in the use of these theoretical models to describe dynamic processes in biology.
- Changbong Hyeon
- & D. Thirumalai
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Article
| Open AccessBackbone rigidity and static presentation of guanidinium groups increases cellular uptake of arginine-rich cell-penetrating peptides
Cell-penetrating peptides can deliver molecular cargoes into living cells, and cross biological membranes by transduction—a non-endocytic mechanism. Here, the transduction efficiency of cyclic arginine-rich peptides is shown to be higher than that of more flexible linear peptides.
- Gisela Lättig-Tünnemann
- , Manuel Prinz
- & M. Cristina Cardoso
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Article
| Open AccessMolecular mechanism for 3:1 subunit stoichiometry of rod cyclic nucleotide-gated ion channels
The assembly mechanisms of heteromeric ion channels are poorly understood. Using a range of techniques, Shuartet al.determine the mechanism by which rod photoreceptor cyclic nucleotide-gated channels assume a 3:1 stoichiometry of CNGA1 and CNGB1 subunits.
- Noah G. Shuart
- , Yoni Haitin
- & William N. Zagotta
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Direct visualization of microtubules using a genetic tool to analyse radial progenitor-astrocyte continuum in brain
The development of radial progenitor cells and astroglia in the cerebral cortex depends on the microtubule cytoskeleton. Eomet al. have developed a new mouse model where the microtubules of astrocytes and radial glia cells are fluorescently tagged, facilitating the detailed study of microtubule dynamics and development in these cells.
- Tae-Yeon Eom
- , Amelia Stanco
- & E.S. Anton
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Article
| Open AccessFreely orbiting magnetic tweezers to directly monitor changes in the twist of nucleic acids
Rotational motion and torsional strain affects DNA replication, transcription and repair. Lipfertet al. have developed a new technique that uses freely orbiting magnetic tweezers to measure equilibrium fluctuations and determine the twist of tethered nucleic acid molecules.
- Jan Lipfert
- , Matthew Wiggin
- & Nynke H. Dekker
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Delay-induced anomalous fluctuations in intracellular regulation
Direct negative feedback decreases fluctuations in homoeostatic control, but intracellular regulatory systems are indirect. Here, an analytical expression is derived to show that indirect feedback in transcription and translation leads to more fluctuations for intermediate delays but not for long delays.
- Andreas Grönlund
- , Per Lötstedt
- & Johan Elf
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Structural mechanisms of DIAP1 auto-inhibition and DIAP1-mediated inhibition of drICE
The inhibitor of apoptosis protein DIAP1 exists in an auto-inhibited conformation, but the details of its molecular interactions are poorly understood. Here, crystal structures reveal the auto-inhibition mechanism of DIAP1 and show how the active form of the protein binds to the effector caspase drICE.
- Xiaochun Li
- , Jiawei Wang
- & Yigong Shi
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Ranking stability and super-stable nodes in complex networks
Pagerank is widely used to rank web content; however, it is unknown how network topology affects its performance. The authors demonstrate that, in random networks, pagerank is sensitive to perturbations in topology, whereas scale-free networks contain a few super-stable nodes whose ranking is exceptionally stable.
- Gourab Ghoshal
- & Albert-László Barabási
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Outlines of the pore in open and closed conformations describe the gating mechanism of ASIC1
The pore gating mechanism of the proton-activated sodium channel ASIC1 is poorly understood. Canessaet al.study the shape of the ion pathway in the ASIC1 channel in its open and closed states, and reveal the opening, closing and desensitization mechanisms of the channel.
- Tianbo Li
- , Youshan Yang
- & Cecilia M. Canessa
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Article
| Open AccessCalcium modulates force sensing by the von Willebrand factor A2 domain
von Willebrand factor (VWF) multimers mediate primary adhesion and aggregation of platelets. Jakobiet al. reveal a calcium-binding site in the VWF-A2 domain, and show that calcium binding encourages folding of the protein and has a role in mechanosensing.
- Arjen J. Jakobi
- , Alireza Mashaghi
- & Eric G. Huizinga
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Article
| Open AccessMechanism of 150-cavity formation in influenza neuraminidase
Group-1 influenza A neuramidase proteins have a 150-cavity that can be targeted by drugs, but the 2009 H1N1 virus neuramidase is not thought to have a 150-cavity. Here, biophysical simulations show that the 2009 H1N1 neuramidase exists in solution with an open 150-cavity, which is stabilized by a salt bridge.
- Rommie E. Amaro
- , Robert V. Swift
- & Robin M. Bush
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Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels
Class I anti-arrhythmic drugs act at cardiac sodium channels and are subdivided into classes Ia-c based on their effects on the electrocardiogram. Here, class Ib drugs are found to rely on cation–pi interactions for their activity, whereas class Ib and Ic drugs rely significantly less on this interaction.
- Stephan A. Pless
- , Jason D. Galpin
- & Christopher A. Ahern
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Atomistic mechanism for the activation and desensitization of an AMPA-subtype glutamate receptor
Upon agonist binding, ionotropic glutamate receptors are activated and then become desensitized, but the detailed molecular events of this process are unclear. Here, molecular dynamics simulations are used to probe how conformational changes of the ligand-binding domain are transmitted to the transmembrane domain.
- Hao Dong
- & Huan-Xiang Zhou
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Article |
Origami-like unfolding of hydro-actuated ice plant seed capsules
Hydro-responsive plant movements have provided inspiration for the design of adaptive materials. Harringtonet al. investigate the hydration-dependent unfolding of ice plant seed capsules and find an origami-like folding pattern, which could aid the development of biomimetic folding structures.
- Matthew J. Harrington
- , Khashayar Razghandi
- & Ingo Burgert
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Article
| Open AccessInteraction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites
The ability of synthetic amyloid β-protein to bind to prion proteins and alter synaptic plasticity has been previously reported. Here the relevance of this binding is investigated in brains of Alzheimer's disease patients and the interaction is shown to be blocked by antibodies to two distinct regions of prion proteins.
- Darragh B. Freir
- , Andrew J. Nicoll
- & John Collinge
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Article
| Open AccessActive microrheology and simultaneous visualization of sheared phospholipid monolayers
Two-dimensional fluid interfaces are ubiquitous, but studying their surface dynamic properties is difficult because of coupling between the film and bulk fluid. Choiet al.combine active microrheology with fluorescence microscopy to image fluid interfaces under applied stress.
- S.Q. Choi
- , S. Steltenkamp
- & T.M. Squires
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Article |
Mutual adaptation of a membrane protein and its lipid bilayer during conformational changes
The detailed interactions of membrane proteins with their lipid environment are poorly understood. Sonntaget al. use low-resolution X-ray crystallographic data and molecular dynamics simulations to study the manner in which the sarcoendoplasmic reticulum Ca2+–ATPase adapts to different membrane environments.
- Yonathan Sonntag
- , Maria Musgaard
- & Lea Thøgersen
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Article |
Two-dimensional enzyme diffusion in laterally confined DNA monolayers
Little is known about the effects of molecular crowding and confinement on biomolecule function. Castronovoet al. investigate the reactions of restriction enzymes with DNA confined in bushy matrices and find that the enzymes enter at the side of the matrix before diffusing two-dimensionally.
- Matteo Castronovo
- , Agnese Lucesoli
- & Giacinto Scoles
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Article |
Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors
N-methyl-D-aspartate receptors mediate excitatory synaptic transmission, and those containing GluN2D subunits have an unusually long deactivation time. Vance et al. show that the conformational variability of the ligand-binding domain and the structure of the activating ligand influence deactivation time.
- Katie M. Vance
- , Noriko Simorowski
- & Hiro Furukawa
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Adhesive water networks facilitate binding of protein interfaces
The formation of hydrophilic protein–protein interactions cannot be explained by charge–charge interactions. Here, molecular simulations reveal that water forms an adhesive hydrogen-bonded network between proteins, stabilizing intermediate states before the bound complex forms.
- Mazen Ahmad
- , Wei Gu
- & Volkhard Helms
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Article
| Open AccessLipid-dependent gating of a voltage-gated potassium channel
Lipid phosphodiesters affect the conformation of certain potassium channels, but the details of the lipid-channel interactions are unclear. Here, the KvAP channel is found to switch from an active to a resting state when the channels are transferred from a phospholipid membrane to a bilayer lacking phosphodiesters.
- Hui Zheng
- , Weiran Liu
- & Qiu-Xing Jiang
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Article
| Open AccessThe structural basis for selective binding of non-methylated CpG islands by the CFP1 CXXC domain
CXXC domain proteins bind to CpG DNA sequences and influence chromatin modification. Xuet al.report crystal structures of the CXXC protein CFP1, a component of the SETD1 histone H3K4 methyl transferase complex, and study the molecular mechanisms of DNA-binding specificity.
- Chao Xu
- , Chuanbing Bian
- & Jinrong Min
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Article
| Open AccessResolving stepping rotation in Thermus thermophilus H+-ATPase/synthase with an essentially drag-free probe
Rotary ATPases FoF1 and VoV1 couple ATP hydrolysis with proton flow. Furuike et al. observe ATP-driven rotation in V1 and VoV1, at submillisecond resolution, and find that rate-limiting reactions in V1 all occur at the same angle, and stator–rotor interactions in Vointroduce additional checkpoints.
- Shou Furuike
- , Masahiro Nakano
- & Ken Yokoyama
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A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa
The CATSPER heteromeric ion channel complex is required for male fertility and six protein components of the complex have been identified. In this study, the authors identify a seventh gene, CATSPERδ, which is necessary for functional CatSper channels and hyperactivated sperm motility.
- Jean-Ju Chung
- , Betsy Navarro
- & David E. Clapham