Biology subjects

Smith, R. W.

Publications and source records attributed to Smith, R. W..

4 recordsLinked to original sources

bioRxiv2026

Ancient Mitogenomes from Belize Provide Insights into the Mobility and Migration of Ancient Communities in Mesoamerica and the Caribbean.

Maya peoples have undergone several largescale demographic transformations over the past 3000 years, including the formation and depopulation of large urban centers, climatic events, and multiple colonial regimes. Archaeological and stable isotope evidence from across the Maya lowlands throughout these periods paints a picture of a demographically mobile population with complex and dynamic relationships among some of the largest urban polities in antiquity. The nature of the genomic relationship between ancient Maya urban centers, as well as their relationship with present-day Maya communities, however, remains under-characterized. Here, we present mitogenomic data of 16 ancient Maya Ancestors recovered from interments in the ancient Maya cities of Caracol and Santa Rita Corozal located in Western and Northern Belize. These ancient data were combined with 110 newly collected contemporary individuals from Northern Belize, along with nearly 600 previously published ancient and contemporary comparative mitogenomes recovered from sites spanning Mesoamerica and the Caribbean to reconstruct paleodemographic and mobility patterns of maternal lineages through time. Our results are consistent with broadly interconnected Maya populations that have maintained maternal genetic continuity across much of the Holocene, and which are not structured by linguistic family.

genetics↗

bioRxiv2022

Small Molecule Modulation of the Archetypal UbiB protein COQ8

Small molecule tools have enabled mechanistic investigations and therapeutic targeting of the protein kinase-like (PKL) superfamily. However, such tools are still lacking for many PKL members, including the highly conserved and disease-related UbiB family. Here, we sought to develop and characterize inhibitor and activator molecules for the archetypal UbiB member, COQ8, whose function is essential for coenzyme Q (CoQ) biosynthesis. Guided by crystallography, activity assays, and cellular CoQ measurements, we repurposed the 4-anilinoquinoline scaffold to selectively inhibit human COQ8A in cells. Second, using 1H-13C HMQC NMR and hydrogen-deuterium exchange mass spectrometry, we reveal that the CoQ precursor mimetic, 2-propylphenol (2-PP), modulates the quintessential UbiB KxGQ domain to increase COQ8A nucleotide affinity and ATPase activity. Our newfound chemical tools promise to lend new mechanistic insights into the activities of these widespread and understudied proteins and to offer potential therapeutic strategies for human diseases connected to their dysfunction.

biochemistry↗

bioRxiv2021

DAZL regulates mRNA deadenylation independently of translation in germ cells

Aberrant gene expression during gametogenesis is one of the factors underlying infertility, which affects roughly 15% of couples worldwide. Deleted-in-Azoospermia-Like (DAZL), a member of the DAZ-gene family, encodes an mRNA-specific regulator of translation which is essential for gametogenesis in both sexes. In this study we show that DAZL controls gene expression in oocytes by regulating the length of the mRNA poly(A) tail, a major determinant of temporal and amplitudinal gene regulation in germ cells, in which gene expression is regulated entirely post-transcriptionally. We show that DAZL does not induce polyadenylation but that binding of DAZL efficiently inhibits mRNA deadenylation induced by oocyte maturation. We reveal that this activity depends on DAZL-mediated recruitment of poly(A)-binding protein, PABP, to the mRNA. Although DAZL also activates mRNA translation via PABP recruitment, mechanistic analysis revealed that neither translation nor translational activation are required for DAZL to stabilise the poly(A) tail, suggesting two mutually independent posttranscriptional roles for the DAZL-PABP complex. We show that recruited PABP must maintain its ability to bind RNA, leading to a model in which DAZL recruits PABP and/or stabilises PABP binding to poly(A) thereby preventing access of deadenylases. These results indicate that the role of DAZL in regulating germ-cell mRNA fate is more complex than previously thought and inform on the poorly understood links between mRNA translation and deadenylation, showing that they can be mechanistically separable.

molecular biology↗

bioRxiv2018

Optogenetic control shows that kinetic proofreading regulates the activity of the T cell receptor

The pivotal task of the immune system is to distinguish between self and foreign antigens. The kinetic proofreading model (KPR) proposes that T cells discriminate self from foreign ligands by the different ligand binding half-lives to the T cell receptor (TCR). It is challenging to test KPR as the available experimental systems fall short of only altering the binding half-lives and keeping other parameters of the ligand-TCR interaction unchanged. We engineered an optogenetic system using the plant photoreceptor phytochrome B to selectively control the dynamics of ligand binding to the TCR by light. Combining experiments with mathematical modeling we find that the ligand-TCR interaction half-life is the decisive factor for activating downstream TCR signaling, substantiating the KPR hypothesis.\n\nOne Sentence SummaryThe half-life of the ligand-T cell receptor complex determines T cell activation.

immunology↗