Biology subjects

Oshima, A.

Publications and source records attributed to Oshima, A..

4 recordsLinked to original sources

bioRxiv2025

Intrinsically Dominant Conformational Diversity in PDZ1 within the Tandem PDZ1-PDZ2 of Human Syntenin-1 Underlined by Crystal Structures.

The intrinsic dynamic asymmetry between homologous PDZ domains in multidomain scaffold proteins offers critical insights into evolutionary mechanisms enabling multivalent partner recognition. Through systematic X-ray crystallographic analysis of human syntenin-1s PDZ1-PDZ2 tandem, we resolve nine high-resolution structures that uncover fundamental differences in conformational plasticity between these sequentially similar domains. Pairwise root-mean-squared deviation (RMSD) analysis of 20 PDZ1 structures across multiple crystal forms reveals substantial structural variability concentrated in the Lys119-Ile125 and Ala181-Glu184 loops - key regions governing ligand specificity within PDZ1s binding cleft. In stark contrast, PDZ2 maintains remarkable structural conservation across all crystallographic environments, indicating divergent evolutionary constraints on these tandem domains. Crucially, comparative analysis of isotropic B-factors demonstrates their inadequacy in capturing the full scope of conformational heterogeneity, emphasizing the necessity of multi-structure comparisons for mapping dynamic landscapes. Molecular dynamics (MD) simulations implemented through GROMACS corroborate these crystallographic observations, showing elevated residue-specific fluctuation (RMSF) values in PDZ1s ligand-binding interface compared to analogous PDZ2 regions. This consistency across experimental and computational approaches confirms that PDZ1s conformational diversity represents an inherent biophysical property rather than crystallographic artifact. The observed dynamic asymmetry suggests a functional division of labor: PDZ1s structural plasticity enables broad ligand recognition via conformational selection mechanisms, while PDZ2s rigid architecture likely stabilizes the tandem domain arrangement. These findings provide an atomic-level rationale for syntenin-1s pleiotropic roles in cellular signaling and establish a structural blueprint for developing domain-selective therapeutics. Given syntenin-1s clinical relevance in cancer metastasis, viral pathogenesis, and neurodevelopmental disorders, our work advances strategies for selectively modulating PDZ1-mediated interactions while preserving PDZ2s scaffolding functions through structure-guided inhibitor design. Highlights{lozenge} Crystal structures of human Syntenin-1s PDZ1-PDZ2 tandem reveal intrinsic conformational plasticity in PDZ1, particularly in ligand-binding loops, contrasting with PDZ2s rigid architecture {lozenge}Pairwise RMSD analysis of 20 PDZ1 structures demonstrates substantial structural variability in the Lys119-Ile125 and Ala181-Glu184 loops, key regions governing ligand specificity {lozenge}Molecular dynamics simulations confirm that PDZ1s conformational diversity is an inherent biophysical property, not a crystallographic artifact {lozenge}The asymmetric dynamics between PDZ1 and PDZ2 suggest a functional division: PDZ1s plasticity enables broad ligand recognition while PDZ2 stabilizes the tandem arrangement {lozenge}These findings provide a structural basis for developing domain-selective Syntenin-1 inhibitors with potential applications in cancer metastasis, viral pathogenesis, and neurodevelopmental disorders

biophysics↗

bioRxiv2024

Modulation of cortico-muscular coupling associated with split-belt locomotor adaptation

Humans can adjust their walking patterns according to the demands of their internal and external environments, referred to as locomotor adaptation. Although significant functional coupling (i.e. cortico-muscular coherence [CMC]) has been shown between cortical and lower-limb muscle activity during steady-state walking, little is known about CMC in locomotor adaptation. Therefore, we investigated the adaptation-dependent modulation of the CMC between the sensorimotor region and the tibialis anterior muscle using a split-belt locomotor adaptation paradigm that can impose an asymmetric perturbation. We hypothesized that the CMC would temporarily decrease after exposure to the asymmetric perturbation and removal of the perturbation because of a mismatch between the predicted and actual sensory feedback. We also hypothesized that the CMC would increase as adaptation and de-adaptation to perturbation progressed because the motor system could become able to predict sensory feedback. Our findings revealed that the CMC temporarily decreased after exposure to and removal of the perturbation. Moreover, the CMC increased with adaptation and de-adaptation to perturbation. Although these results depend on the leg, frequency bands, and gait phases, they partially support our hypothesis. These findings suggest that flexible updating of cortico-muscular coupling in the motor system is a key mechanism underlying locomotor adaptation in humans. The results from our study on healthy young individuals contribute to the understanding of neuromuscular control of gait and provide valuable insight for optimising gait rehabilitation. Key pointsO_LILocomotor adaptation plays a crucial role in our daily activities and gait rehabilitation. C_LIO_LIAlthough knowledge regarding the brain and muscle activities associated with locomotor adaptation has been accumulated, little is known about the functional coupling of the brain and muscle activities. C_LIO_LIUsing high-density EEG and lower limb EMG, we demonstrated the modulation of cortico-muscular coherence between the sensorimotor region and the tibialis anterior muscle with adaptation and de-adaptation during a split-belt treadmill walking paradigm. C_LIO_LIOur findings suggest that flexible updating of cortico-muscular coupling in the motor system underlies locomotor adaptation in humans. C_LIO_LIUnderstanding the human brains control of muscles during split-belt locomotor adaptation will deepen our knowledge of neuromuscular control of gait and provide valuable insights for gait rehabilitation. C_LI

neuroscience↗

bioRxiv2023

A hyperpolarizing neuron recruits undocked innexin hemichannels to transmit neural information in Caenorhabditis elegans

While depolarization of neuronal membrane is known to evoke the neurotransmitter release from synaptic vesicles, hyperpolarization is regarded as a resting state of chemical neurotransmission. Here we report that hyperpolarizing neurons can actively signal neural information by employing undocked hemichannels. We show that UNC-7, a member of the innexin family in Caenorhabditis elegans, functions as a hemichannel in thermosensory neurons and transmits temperature information from the thermosensory neurons to their post-synaptic interneurons. By monitoring neural activities in freely behaving animals, we find that hyperpolarizing thermosensory neurons inhibit the activity of the interneurons and that UNC-7 hemichannels regulate this process. UNC-7 is required to control thermotaxis behavior and functions independently of synaptic vesicle exocytosis. Our findings suggest that innexin hemichannels mediate neurotransmission from hyperpolarizing neurons in a manner that is distinct from the synaptic transmission, expanding the way of neural circuitry operations.

neuroscience↗

bioRxiv2021

Structure and dynamics of Odinarchaeota tubulin and the implications for eukaryotic microtubule evolution

Tubulins are critical for the internal organization of eukaryotic cells, and understanding their emergence is an important question in eukaryogenesis. Asgard archaea are the closest known prokaryotic relatives to eukaryotes. Here, we elucidated the apo and nucleotide-bound X-ray structures of an Asgard tubulin from hydrothermal-living Odinarchaeota (OdinTubulin). The GTP-bound structure resembles a microtubule protofilament, with GTP bound between subunits, coordinating the "+" end subunit through a network of water molecules and unexpectedly by two cations. A water molecule is located suitable for GTP hydrolysis. Time course crystallography and electron microscopy revealed conformational changes on GTP hydrolysis. OdinTubulin forms tubules at high temperatures, with short curved protofilaments coiling around the tubule circumference, more similar to FtsZ, rather than running parallel to its length, as in microtubules. Thus, OdinTubulin represents an evolution intermediate between prokaryotic FtsZ and eukaryotic microtubule-forming tubulins.

evolutionary biology↗