Biology subjects

Sakuma, K.

Publications and source records attributed to Sakuma, K..

7 recordsLinked to original sources

bioRxiv2026

Age-Related Remodeling of Cross-Tissue Transcriptional Coordination in the Human Motor System

How aging is coordinated across the anatomically distinct tissues that collectively constitute the human motor system remains unclear. Here, we integrated data from the Genotype-Tissue Expression (GTEx) project and Gene Expression Omnibus (GEO), comprising 7,145 samples from 15 human tissues spanning three functional levels of motor control, signal transmission, and peripheral execution, and reconstructed age-related transcriptional trajectories using generalized additive models. Most age-related genes were shared across multiple tissues, yet their direction of regulation, effect magnitude, and temporal trajectories showed marked tissue specificity. Despite the clear central-to-peripheral functional organization of the motor system, transcriptional aging did not follow a stable temporal sequence or spatial gradient along this functional chain. Instead, cross-tissue transcriptional synchrony progressively increased from early to mid-adulthood, reached a relatively high level around midlife, and subsequently declined in later life, a pattern supported at both the gene and pathway levels. This late-life loss of coordination was selective, prominently involving the peripheral nerve-skeletal muscle axis and multiple tissue connections involving the striatum. Our analyses indicate that transcriptional aging of the human motor system is characterized by tissue-specific responses built upon a broadly shared molecular basis of aging, together with age-dependent reorganization of cross-tissue coordination and selective late-life decoupling.

systems biology↗

bioRxiv2026

Neuronal stop-codon readthrough is associated with ribosome pausing and alters protein localization in Drosophila

Stop-codon readthrough (RT) diversifies proteomes and is particularly prominent in neurons, suggesting its importance in nervous systems. However, the regulatory logic that specifies neuronal RT and the structural and cellular consequences of the resulting C-terminal protein extensions remain poorly understood. Here we leverage neuron-specific ribosome profiling datasets in Drosophila to construct an in vivo atlas of 163 neuronal RT transcripts. Sequence- based modeling distinguished RT from non-RT transcripts and highlighted an extended post-stop region enriched for stable predicted RNA structures. Beyond these cis-associated features, ribosome-footprint analysis revealed pronounced stop-codon pausing on RT transcripts, accompanied by upstream periodic peaks from the stop codon consistent with ribosome queuing. At the protein level, neuronal RT appended polypeptides enriched with polar residues and intrinsically disordered regions (IDRs). Finally, an in vivo dual-color reporter showed that RT of the RNA-binding protein Bru3 alters localization from the nucleus to cytoplasmic granules. Together, our results suggest that neuronal RT is associated with structured post-stop RNA regions that reshape termination dynamics and can produce IDR-rich C-terminal protein extensions with distinct subcellular localization.

molecular biology↗

bioRxiv2026

Genetic population structure and demographic history of Pacific cod in Japanese waters: Implications for stock identification using SNP markers

Pacific cod is a key species in North Pacific fisheries, and its stock assessment and management units are separated according to biological, geographical, and administrative information. Understanding the fine-scale genetic population structure of this species is crucial for effective management, particularly in regions such as Japan, where complex coastal geography and localised fisheries management prevail. Therefore, in this study, we analysed genome-wide single nucleotide polymorphisms (SNPs; 6,035 loci) in 496 individuals of Pacific cod sampled from 33 sites around the Japanese archipelago via genotyping by random amplicon sequencing-direct (GRAS-Di) analysis. Our analyses revealed three major genetic groups: Japanese Broad Range, Northernmost Honshu-Hokkaido (NHH), and Western Sea of Japan groups. These groups exhibited significant genetic differentiation (global FST = 0.056), distinct levels of nucleotide diversity, and group-specific genome-wide patterns of Tajimas D. Moreover, demographic history reconstruction based on whole-genome sequencing of three representative individuals revealed that each genetic group followed distinct demographic trajectories since the last glacial period. Importantly, the NHH group, related to the Mutsu Bay spawning aggregation and previously shown to exhibit strong natal homing in tagging surveys, was genetically identified for the first time in this study. Isolation-by-distance was observed across Japanese waters and within the Japanese Broad Range group, but not within the NHH group, suggesting that gene flow is generally restricted by geographic distance, except within the NHH group. To evaluate the potential for genetic stock identification, we extended a resampling-based cross-validation framework by incorporating outlier detection to assess marker selection strategies. Over 500 background SNPs were required to achieve >90% assignment accuracy for genetic stock identification, whereas only eight or more outlier SNPs showed comparable performance. These findings suggest that carefully selected SNP panels, particularly those including outlier loci, substantially improve stock discrimination. Overall, our study demonstrates the fine-scale genetic structure and demographic history of Pacific cod in Japanese waters and highlights the utility of practical marker strategies for enhancing the biological realism of fisheries assessment and supporting sustainable fisheries management.

genetics↗

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↗

bioRxiv2023

Dual-wield NTPase: a novel protein family mined from AlphaFold DB

AlphaFold protein structure database (AlphaFold DB) archives a vast number of predicted models. We conducted systematic data mining against AlphaFold DB and discovered an uncharacterized P-loop NTPase family. The structure of the protein family was surprisingly novel, showing an atypical topology for P-loop NTPases, noticeable two-fold symmetry and two pairs of independent putative active sites. Our findings show that structural data mining is a powerful approach to identifying undiscovered protein families.

bioinformatics↗

bioRxiv2021

Design of complicated all-α protein structures

A wide range of de novo protein structure designs have been achieved, but the complexity of naturally occurring protein structures is still far beyond these designs. To expand the diversity and complexity of de novo designed protein structures, we sought to develop a method for designing "difficult-to-describe"-helical protein structures composed of irregularly aligned -helices like globins. Backbone structure libraries consisting of a myriad of -helical structures with 5- or 6-helices were generated by combining 18 helix-loop-helix motifs and canonical -helices, and five distinct topologies were selected for de novo design. The designs were found to be monomeric with high thermal stability in solution and fold into the target topologies with atomic accuracy. This study demonstrated that complicated -helical proteins are created using typical building blocks. The method we developed would enable us to explore the universe of protein structures for designing novel functional proteins.

biophysics↗

bioRxiv2021

Limitations of the ABEGO representation: ambiguity between αα-corner and αα-hairpin

ABEGO is a coarse-grained representation for polypeptide backbone dihedral angles. The Ramachandran map is divided into four segments denoted as A, B, E, and G to represent the local conformation of polypeptide chains in the character strings. Although the ABEGO representation is widely used in structural informatics and protein design, it cannot capture minor differences in backbone dihedral angles, which potentially leads to ambiguity between two structurally distinct fragments. Here, we show a nontrivial example of two local motifs that could not be distinguished by their ABEGO representations. We found that two well-known local motifs -hairpins and -corners are both represented as -GBB- and thus indistinguishable in the ABEGO representation, although they show distinct arrangements of the flanking -helices. We also found that -GBB- motifs caused a loss of efficiency in the ABEGO-based fragment-assembly simulations for protein backbone design. Nevertheless, we designed amino-acid sequences that were predicted to fold into the target topologies that contained these -GBB- motifs. Our finding that certain local motifs bottleneck the ABEGO-based fragment-assembly simulations for construction of backbone structures suggests that finer representations of backbone torsion angles are required for efficiently generating diverse topologies containing such indistinguishable local motifs.

bioinformatics↗