U. Benjamin Kaupp

Center of Advanced European Studies and Research | CAESAR · Department of Molecular Sensory Systems

Navigation of dendritic cells (DCs) from the site of infection to lymphoid organs is guided by concentration gradients of CCR7 ligands. How cells interpret chemokine gradients and how they couple directional sensing to polarization and persistent chemotaxis has remained largely elusive. Previous experimental systems were limited in the ability to c...

Cyclic nucleotide-gated (CNG) channels play a central role in rod and cone photoreceptors of the vertebrate retina. In photoreceptors, light triggers a series of biochemical reactions that ultimately close CNG channels and evoke a brief voltage pulse, a signal that is later passed on to the brain. Malfunction of CNG channels can lead to loss of vis...

In rod photoreceptors of the retina, the cyclic nucleotide-gated (CNG) channel is composed of three CNGA and one CNGB subunits, and it closes in response to light activation to generate an electrical signal that is conveyed to the brain. Here we report the cryo-EM structure of the closed state of the native rod CNG channel isolated from bovine reti...

Fluorescent probes that change their spectral properties upon binding to small biomolecules, ions, or changes in the membrane potential (V m) are invaluable tools to study cellular signaling pathways. Here, we introduce a novel technique for simultaneous recording of multiple probes at millisecond time resolution: frequency-and spectrally-tuned mul...

The recently reported structure of the human CNGA1/CNGB1 CNG channel in the open state (Xue et al., 2021a) shows that one CNGA1 and one CNGB1 subunit do not open the central hydrophobic gate completely upon cGMP binding. This is different from what has been reported for CNGA homomeric channels (Xue et al., 2021b, Zheng et al., 2020). In seeking to...

Many biological processes happen on a nano- to millimeter scale and within milliseconds. Established methods such as confocal microscopy are suitable for precise 3D recordings but lack the temporal or spatial resolution to resolve fast 3D processes and require labeled samples. Multifocal imaging (MFI) allows high-speed 3D imaging but is limited by...

The eukaryotic flagellum propels sperm cells and simultaneously detects physical and chemical cues that modulate the waveform of the flagellar beat. Most previous studies have characterized the flagellar beat and swimming trajectories in two space dimensions (2D) at a water/glass interface. Here, using refined holographic imaging methods, we report...

The function of proteins is linked to their conformations that can be resolved with several high-resolution methods. However, only a few methods can provide the temporal order of intermediates and conformational changes, with each having its limitations. Here, we combine pulsed electron-electron double resonance spectroscopy with a microsecond free...

Significance Understanding the evolution of sex determination mechanisms and sex chromosomes is of fundamental importance in biology. Here we have reconstructed the evolution of the sex-determining region in the Atlantic herring. The region is small and contains only three intact genes. The candidate sex-determining factor BMPR1BBY is an evolutiona...

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Mammalian oocytes are enveloped by the zona pellucida (ZP), an extracellular matrix of glycoproteins. In sperm, stimulation with ZP proteins evokes a rapid Ca2+ influx via the sperm-specific, pH-sensitive Ca2+ channel CatSper. However, the physiological role and molecular mechanisms underlying ZP-dependent activation of CatSper are unknown. Here, w...

Significance We discovered a subfamily of voltage-gated ion channels, called HCN-like channels, consisting of two members, HCNL1 and HCNL2. In contrast to classic pacemaker HCN channels in the heart and brain, HCNL1 conducts protons rather than potassium or sodium ions. The pore domain, which exists in most voltage-gated channels, is nonconducting....

Many biological processes happen on a nano- to millimeter scale and within milliseconds. Established methods such as confocal microscopy are suitable for precise 3D recordings but lack the temporal or spatial resolution to resolve fast 3D processes and require labeled samples. Multifocal imaging (MFI) allows high-speed 3D imaging but suffers from t...

Activity and autonomous motion are fundamental in living and engineering systems. This has stimulated the new field of ‘active matter’ in recent years, which focuses on the physical aspects of propulsion mechanisms, and on motility-induced emergent collective behavior of a larger number of identical agents. The scale of agents ranges from nanomotor...

Sperm are highly specialized cells, which have been subject to substantial evolutionary pressure. Whereas some sperm features are highly conserved, others have undergone major modifications. Some of these variations are driven by adaptation to mating behaviours or fitness at the organismic level. Others represent alternative solutions to the same t...

Navigation of sperm in fluid flow, called rheotaxis, provides long-range guidance in the mammalian oviduct. The rotation of sperm around their longitudinal axis (rolling) promotes rheotaxis. Whether sperm rolling and rheotaxis require calcium (Ca 2+) influx via the sperm-specific Ca 2+ channel CatSper, or rather represent passive biomechanical and...

Cilia serve as cellular antennae that translate sensory information into physiological responses. In the sperm flagellum, a single chemoattractant molecule can trigger a Ca2+ rise that controls motility. The mechanisms underlying such ultra-sensitivity are ill-defined. Here, we determine by mass spectrometry the copy number of nineteen chemosensory...

Activity and autonomous motion are fundamental in living and engineering systems. This has stimulated the new field of active matter in recent years, which focuses on the physical aspects of propulsion mechanisms, and on motility-induced emergent collective behavior of a larger number of identical agents. The scale of agents ranges from nanomotors...

Sperm from sea urchins are attracted by chemical cues released by the egg—a mechanism called chemotaxis. We describe here the signaling pathway and molecular components endowing sperm with single-molecule sensitivity. Chemotactic signaling and behavioral responses occur on a timescale of a few milliseconds to seconds. We describe the techniques and...

Study question: Does the chemosensory activation of CatSper Ca2+ channels in human sperm give rise to additive, sub-additive or even synergistic actions among agonists? Summary answer: We show that oviductal ligands and endocrine disrupting chemicals (EDCs) activate human CatSper highly synergistically. What is known already: In human sperm, t...

Voltage-sensing (VSD) and cyclic nucleotide-binding domains (CNBD) gate ion channels for rapid electrical signaling. By contrast, solute carriers (SLCs) that passively redistribute sub-strates are gated by their substrates themselves. Here, we study the orphan sperm-specific solute carriers SLC9C1 that feature a unique tripartite structure: an exch...

Background and purpose: Sperm from many species share the sperm-specific Ca2+ channel CatSper (cation channel of sperm) that controls the intracellular Ca2+ concentration and, thereby, the swimming behaviour. A growing body of evidence suggests that the mechanisms controlling CatSper activity and the role of the channel during fertilization differ...

Grant: This work was supported by German Research Foundation Grants CRU326 (to T.S. and F.T.) and SFB1089 (to U.B.K.); Cells-in- Motion Cluster of Excellence (Münster) Grant CiM20027 (to T.S.); and a research fellowship from the European Society for Paediatric Endocrinology (to I.V.W.).

Sperm are propelled by bending waves travelling along the flagellum. During steering in gradients of sensory cues, sperm adjust the flagellar beat waveform. Symmetric and asymmetric beat waveforms produce straight and curved swimming paths, respectively. Two different mechanisms controlling the flagellar beat have been proposed: average intrinsic c...

Fertilization is exceptionally complex and, depending on the species, happens in entirely different environments. External fertilizers in aquatic habitats, like marine invertebrates or fish, release their gametes into the seawater or freshwater, whereas sperm from most internal fertilizers like mammals cross the female genital tract to make their w...

Key points: In human sperm, proton flux across the membrane is controlled by the voltage-gated proton channel Hv1. We show that sperm harbour both Hv1 and an N-terminally cleaved isoform termed Hv1Sper. The pH-control of Hv1Sper and Hv1 is distinctively different. Hv1Sper and Hv1 can form heterodimers that combine features of both constituents. Cl...

Many cells and microorganisms have evolved a motility apparatus to explore their surroundings. For guidance, these biological microswimmers rely on physical and chemical cues that are transduced by cellular pathways into directed movement – a process called taxis. Only few biological microswimmers have been studied as detailed as sperm from sea urc...

For a given sensory cell type, signaling motifs are rather uniform across phyla. By contrast, sperm from different species use diverse repertoires of sperm-specific signaling molecules and even closely related protein isoforms feature different properties and serve different functions. This surprising diversity has consequences for strategies in fe...

Locomotion of autonomous microswimmers is a fascinating field at the cutting edge of science. It combines the biophysics of self- propulsion via motor proteins, artificial propulsion mechanisms, swimming strategies at low Reynolds numbers, the hydrodynamic interaction of swimmers, and the collective motion and synchronisation of large numbers of ag...

Ligand-protein binding processes are essential in biological systems. A well-studied system is the binding of cyclic adenosine monophosphate to the cyclic nucleotide binding domain of the bacterial potassium channel MloK1. Strikingly, the measured on-rate for cyclic adenosine monophosphate binding is two orders of magnitude slower than a simple Smo...

Characteristics of mlCNBD-FRET.Binding affinities and the cerulean lifetime are shown as mean ± S.D.; n numbers are indicated.DOI: http://dx.doi.org/10.7554/eLife.14052.010

Characteristics of other cAMP biosensors.DOI: http://dx.doi.org/10.7554/eLife.14052.011

Fertility parameters of mlCNBD-FRET transgenic males.For matings, heterozygous males have been crossed with wild-type females. All data are represented as mean ± S.D., n numbers are indicated.DOI: http://dx.doi.org/10.7554/eLife.14052.008

The cellular messenger cAMP regulates multiple cellular functions, including signaling in cilia and flagella. The cAMP dynamics in these subcellular compartments are ill-defined. We introduce a novel FRET-based cAMP biosensor with nanomolar sensitivity that is out of reach for other sensors. To measure cAMP dynamics in the sperm flagellum, we gener...

Dendritic cells (DCs) are an essential component of the mammalian immune system because they link the innate and the adaptive immune responses. They are sentinels that patrol and scan the peripheral tissue where they capture pathogen-derived antigens at the site of infection. After this, they migrate to the secondary lymphoid organs, where they pri...

Unlabelled: Dendritic voltage-gated ion channels profoundly shape the integrative properties of neuronal dendrites. In epilepsy, numerous changes in dendritic ion channels have been described, all of them due to either their altered transcription or phosphorylation. In pilocarpine-treated chronically epileptic rats, we describe a novel mechanism t...

Guanylate cyclase (GC) is an enzyme that catalyses the synthesis of cGMP from GTP. Arbacia punctulata sperm use a GC chemoreceptor for sperm chemotaxis. The chemoreceptor is able to sense single resact molecules, a derived oocyte-derived peptide that serves as chemoattractant. This high sensitivity is due to a high affinity of the GC for resact, an...

Guanylate cyclase (GC) is an enzyme that catalyses the synthesis of cGMP from GTP. Arbacia punctulata sperm use a GC chemoreceptor for sperm chemotaxis. The chemoreceptor is able to sense single resact molecules, a derived oocyte-derived peptide that serves as chemoattractant. This high sensitivity is due to a high affinity of the GC for resact, an...

Sperm require a sense of direction to locate the egg for fertilization. They follow gradients of chemical and physical cues provided by the egg or the oviduct. However, the principles underlying three-dimensional (3D) navigation in chemical landscapes are unknown. Here using holographic microscopy and optochemical techniques, we track sea urchin sp...

Many cells probe their environment for chemical cues. Some cells respond to picomolar concentrations of neuropeptides, hormones, pheromones, or chemoattractants. At such low concentrations, cells encounter only a few molecules. The mechanistic underpinnings of single-molecule sensitivity are not known for any eukaryotic cell. Sea urchin sperm offer...

The visual pigment rhodopsin belongs to the family of G protein-coupled receptors that can form higher oligomers. It is controversial whether rhodopsin forms oligomers and whether oligomers are functionally relevant. Here, we study rhodopsin organization in cryosections of dark-adapted mouse rod photoreceptors by cryoelectron tomography. We identif...

Ligand-protein binding processes play an essential role in biological systems, be it signalling immune response or enzymatic activity. An experimentally well-studied system is the binding of cyclic adenosine monophosphate (cAMP) at the cyclic nucleotide binding domain (CNBD) of the bacterial potassium channel MloK1. The channel's conductivity is mo...

The Prm1-bPAC mouse model shows no change in fertility parameters.Data are given as mean ± s.d.; n = number of experiments.DOI: http://dx.doi.org/10.7554/eLife.05161.004

Sperm guidance is controlled by chemical and physical cues. In many species, Ca(2+) bursts in the flagellum govern navigation to the egg. In Arbacia punctulata, a model system of sperm chemotaxis, a cGMP signaling pathway controls these Ca(2+) bursts. The underlying Ca(2+) channel and its mechanisms of activation are unknown. Here, we identify CatS...

Hyperpolarization activated and cyclic nucleotide-gated (HCN) ion channels as well as cyclic nucleotide-gated (CNG) ion channels are essential for the regulation of cardiac cells, neuronal excitability, and signaling in sensory cells. Both classes are composed of four subunits. Each subunit comprises a transmembrane region, intracellular N- and C-t...

Guanylyl cyclases (GCs), which synthesize the messenger cyclic guanosine 3',5'-monophosphate, control several sensory functions, such as phototransduction, chemosensation, and thermosensation, in many species from worms to mammals. The GC chemoreceptor in sea urchin sperm can decode chemoattractant concentrations with single-molecule sensitivity. T...

Synthetic endocrine disrupting chemicals (EDCs), omnipresent in food, household, and personal care products, have been implicated in adverse trends in human reproduction, including infertility and increasing demand for assisted reproduction. Here, we study the action of 96 ubiquitous EDCs on human sperm. We show that structurally diverse EDCs activ...

Indicators of merit for the mass spectrometric results. DOI: http://dx.doi.org/10.7554/eLife.01438.020

Sperm are equipped with a unique set of ion channels that orchestrate fertilization. In mouse sperm, the principal K+ current (IKSper) is carried by the Slo3 channel, which sets the membrane potential (Vm) in a strongly pHi-dependent manner. Here, we show that IKSper in human sperm is activated weakly by pHi and more strongly by Ca2+. Corresponding...

Sperm are guided to the egg by a gradient of chemical attractants - a process called chemotaxis. The binding of the chemoattractant to receptors on the surface of the flagellum triggers a cascade of signaling events that eventually lead to an influx of Ca(2+) ions. Based on these Ca(2+) surges, which control the waveform of the flagellar beat, sper...

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Protein functions rely on protein motions. Protein structures, obtained with X-ray diffraction or NMR, reveal mostly static pictures of structure-function relation. To connect structural changes of proteins with function, we need to look at events happening in real time, i.e. the dynamics of the processes.We have chosen mlCNBD as a model protein to...

Significance Activity of the small GTPase Ras (rat sarcoma) needs to be tightly regulated because aberrant activity has a potent oncogenic effect, causing several forms of cancer as well as developmental disorders known as RASopathies. We have identified the ezrin, radixin, and moesin protein family as a previously unknown component in the control...

Author Summary New life begins with the fusion of a sperm and an oocyte. During fertilization, sperm cope with demanding endeavors: they have to locate the egg by directed swimming and penetrate the oocyte's vestments. Cyclic nucleotides and their targets represent one of the most ancient signaling systems and are important for the control of sperm...

Introduction Within the female tract sperm must use functionally different behaviours at different times. Motility is controlled primarily by intracellular Ca²⁺ concentration ([Ca²⁺]i), increased [Ca²⁺]i apparently switching sperm from linear swimming to more complex motility types. CatSper, which is expressed only in the flagellum of sperm, is bel...

Behavioral traits of sperm are adapted to the reproductive strategy that each species employs. In polyandrous species, spermatozoa often form motile clusters, which might be ad-vantageous for competing with sperm from other males [1]. Despite this presumed advantage for reproductive success [2, 3], little is known about how sperm form such function...