Biology subjects

Raia, P.

Publications and source records attributed to Raia, P..

7 recordsLinked to original sources

bioRxiv2026

Milankovic cycles and Cultural Evolution as Important Catalysts for Hominin Genetic Diversification

Climate variability is widely considered a key driver of human evolution, yet the mechanisms linking long-term climate change driven by Milankovi[c] cycles to hominin demography and genetic diversity remain elusive. Here we couple an agent-based demographic model, incorporating an idealized genetic marker, cultural dynamics, and a realistic Pleistocene climate framework, to quantify how astronomically forced climate and vegetation variability shaped the genetic structure of African hominins over the past 1.9 Myr. We show that warm early Pleistocene climates sustained a continent-wide network of genetically diverse demes until ~900 ka. The subsequent decline in atmospheric CO2, associated cooling, and reduced vegetation during the Mid-Pleistocene Transition triggered widespread demographic collapse, with populations surviving only in southern and eastern Africa. This reorganization in population structure leads to a decline in simulated genetic diversity, consistent in timing with genomic and archeological evidence. Introducing cultural innovations in the model, represented as enhanced carrying capacity, enables hominin populations to recover from this diversity bottleneck, adapt to increasingly harsh late Pleistocene environments and long glacial periods, rapidly expand across Africa during interglacials, and ultimately disperse into Eurasia. Our results identify Milankovi[c]-scale climate forcing and cultural growth as important catalysts of hominin population structure and genetic diversification.

evolutionary biology↗

bioRxiv2026

Plant Kelch phosphatases are Ser/Thr phosphatases involved in cell cycle regulation

Brassinosteroids (BRs) are plant steroid hormones sensed by the membrane receptor kinase BRI1. Activation of BRI1 leads to the dephosphorylation of BZR1/BES1 transcription factors. Overexpression of the Kelch phosphatase BRI1 SUPPRESSOR 1 (BSU1) rescued the growth defects of bri1 mutants. Subsequent studies identified BSU1 as a protein tyrosine phosphatase, which promotes BR signaling by dephosphorylating a phosphotyrosine in the glycogen synthase kinase 3 BIN2. Crystal structures of the BSU1 phosphatase domain now reveal a high degree of structural similarity to protein phosphatase 1 (PP1), a eukaryotic serine/threonine phosphatase. Consistently, BSU1 efficiently dephosphorylated phosphothreonine- and phosphoserine-containing substrate peptides, but showed no detectable activity toward BIN2 and other phosphotyrosine substrates. A catalytically inactive BSU1 phosphatase domain suppresses the growth phenotypes of the Arabidopsis bri1-5 mutant and binds the BSU1 homologs BSL1-3. bsu1 and bsu1 bsl1 bsl2/3 loss-of-function mutants display wild-type-like BR responses, but exhibit stomatal patterning and fertility defects. Importantly, the PP1-like C-terminal tail of BSU1 is phosphorylated at Thr785 by a cyclin-dependent kinase complex. The phosphorylated tail binds to the BSU1 substrate-binding grooves, blocking access to the active site. Mutation of Thr785 to alanine activates BSU1, suggesting that Kelch phosphatases and PP1 share a common regulatory mechanism. Deletion of the Marchantia polymorpha Kelch phosphatase MpBSLM results in an undifferentiated cell mass phenotype, associated with the over-activation of a cell cycle reporter. Taken together, our experiments suggest that plant Kelch phosphatases act as PP1-like cell cycle regulators, rather than as tyrosine phosphatases in brassinosteroid signaling. (243 words) Significance StatementBrassinosteroid hormones initiate a well-characterized signaling pathways in plants. While the early signaling events at the plasma membrane have been thoroughly examined, the precise sequence of molecular events that comprise the cytoplasmic signaling cascade is less well-understood. Here, the molecular function of the Kelch protein phosphatase BSU1 is re-evaluated. Previous reports have indicated that BSU1 dephosphorylates the GSK3 kinase BIN2 on a central tyrosine residue. However, structural, quantitative enzyme kinetic, and genetic analyses now suggest that BSU1 is a PP1-like serine/threonine phosphatase involved in cell cycle control rather than a tyrosine phosphatase involved in BIN2 de-phosphorylation. The regulation of BSU1 by a cyclin-dependent kinase complex and the role of Kelch phosphatases in cell cycle progression in Marchantia polymorpha are experimentally characterized. (121 words)

plant biology↗

bioRxiv2024

An accelerating, decreasing phylogenetic trend in SARS-CoV-2 genome compositional heterogeneity during the pandemic

The rapid evolution of SARS-CoV-2 during the pandemic, driven by a plethora of mutations, many of which enable the virus to evade host resistance, has likely altered its genomes compositional structure (i.e. the arrangement of compositional domains of varying lengths and nucleotide frequencies within the genome). To explore this hypothesis, we summarize the evolutionary effects of these mutations by computing the Sequence Compositional Complexity (SCC) in random datasets of fully sequenced genomes. Phylogenetic ridge regression of SCC against time reveals a striking downward evolutionary trend, as well as an increasing rate of change, suggesting the ongoing adaptation of the viruss genome structure to the human host. Other genomic features, such as strand asymmetry, the effective number of K-mers, and the depletion of CpG dinucleotides, each linked to the viruss adaptation to its human host, also exhibit decreasing phylogenetic trends over the course of the pandemic, along with strong phylogenetic correlations to SCC. Overall, our findings suggest an accelerated, genome-wide evolutionary trend toward a more symmetric and homogeneous genome compositional structure in SARS-CoV-2.

evolutionary biology↗

bioRxiv2024

A GAF domain mediates inositol pyrophosphate substrate channeling in PPIP5K phosphatases

Inositol pyrophosphates (PP-InsPs) are highly phosphorylated nutrient messengers. The final step of their biosynthesis is catalyzed by diphosphoinositol pentakisphosphate kinase (PPIP5K) enzymes, which are conserved among fungi, plants, and animals. PPIP5Ks contain an N-terminal kinase domain that generates the active messenger 1,5-InsP8 and a C-terminal phosphatase domain that participates in PP-InsP catabolism. The balance between kinase and phosphatase activities controls the cellular levels and signaling capacity of 1,5-InsP8. Here, we present crystal structures of the apo and substrate-bound Vip1 phosphatase domain from S. cerevisiae (ScVip1PD). ScVip1PD is a phytase-like inositol 1-pyrophosphate phosphatase with two conserved histidine phosphatase catalytic motifs. The enzyme has a strong preference for 1,5-InsP8 and is inhibited by inorganic phosphate. ScVip1PD has an -helical insertion domain stabilized by a structural Zn2+ binding site, and a unique GAF signaling domain that exists in an open and closed state, allowing channeling of the 1,5-InsP8 substrate to the active site. Mutations that alter the active site, that restrict the movement of the GAF domain or that modify the charge of the substrate channel, significantly inhibit the activity of the yeast enzyme in vitro, and the function of the Arabidopsis PPIP5K VIH2 in planta. Structural analyses of full-length PPIP5Ks suggest that the kinase and phosphatase are independent enzymatic modules. Taken together, our work reveals the structure, enzymatic mechanism and regulation of eukaryotic PPIP5K phosphatases.

biochemistry↗

bioRxiv2023

Structural Basis of μ-Opioid Receptor-Targeting by a Nanobody Antagonist

The -opioid receptor (OR), a prototypical member of the G protein-coupled receptor (GPCR) family, is the molecular target of opioid analgesics such as morphine and fentanyl. Due to the limitations and severe side effects of currently available opioid drugs, there is considerable interest in developing novel modulators of OR function. Most GPCR ligands today are small molecules, however biologics, including antibodies and nanobodies, are emerging as alternative therapeutics with clear advantages such as affinity and target selectivity. Here, we describe the nanobody NbE, which selectively binds to the OR and acts as an antagonist. We functionally characterize NbE as an extracellular and genetically encoded {micro}OR ligand and uncover the molecular basis for {micro}OR antagonism by solving the cryo-EM structure of the NbE-{micro}OR complex. NbE displays a unique ligand binding mode and achieves {micro}OR selectivity by interactions with the orthosteric pocket and extracellular receptor loops. Based on a {beta}-hairpin loop formed by NbE that deeply inserts into the {micro}OR and centers most binding contacts, we design short peptide analogues that retain {micro}OR antagonism. The work illustrates the potential of nanobodies to uniquely engage with GPCRs and describes novel OR ligands that can serve as a basis for therapeutic developments.

molecular biology↗

bioRxiv2022

The emergence of variants with increased fitness accelerates the slowdown of genome sequence heterogeneity in the SARS CoV 2 coronavirus

Since the outbreak of the COVID-19 pandemic, the SARS-CoV-2 coronavirus has accumulated an important amount of genetic and genomic variability through mutation and recombination events. To test evolutionary trends that could inform us on the adaptive process of the virus to its human host, we summarize all this sequence variability by computing the Sequence Compositional Complexity (SCC) in more than 23,000 high-quality coronavirus genome sequences from across the globe, covering the period spanning from the start of the pandemic in December 2019 to March 2022. In early samples, we found no statistical support for any trend in SCC values over time, although the virus as a whole appears to evolve faster than Brownian Motion expectation. However, in samples taken after the first Variant of Concern (VoC) with higher transmissibility (Alpha) emerges, and controlling for phylogenetic and sampling effects, we were able to detect a statistically significant trend for decreased SCC values over time. SARS-CoV-2 evolution towards lower values of genome heterogeneity is further intensified by the emergence of successive, widespread VoCs. Concomitantly to the temporal reduction in SCC, its absolute evolutionary rate kept increasing toward the present, meaning that the SCC decrease itself accelerated over time. As compared to Alpha or Delta variants, the currently dominant VoC, Omicron, shows much stronger trends in both SCC values and rates over time. These results indicate that the increases in fitness of variant genomes associated to a higher transmissibility leads to a reduction of their genome sequence heterogeneity, thus explaining the general slowdown of SCC along with the pandemic course.

genomics↗

bioRxiv2020

Structural basis for the increased processivity of D-family DNA polymerases in complex with PCNA

Replicative DNA polymerases (DNAPs) have evolved the ability to copy the genome with high processivity and fidelity. In Eukarya and Archaea, the processivity of replicative DNAPs is greatly enhanced by its binding to the proliferative cell nuclear antigen (PCNA) that encircles the DNA. We determined the cryo-EM structure of the DNA-bound PolD-PCNA complex from Pyrococcus abyssi at 3.77[A]. Using an integrative structural biology approach - combining cryo-EM, X-ray crystallography and protein-protein interaction measurements - we describe the molecular basis for the interaction and cooperativity between a replicative DNAP and PCNA with an unprecedented level of detail. PolD recruits PCNA via a complex mechanism, which requires two different PIP-boxes. We infer that the second PIP-box, which is shared with the eukaryotic Pol replicative DNAP, plays a dual role in binding either PCNA or primase, and could be a master switch between an initiation phase and a processive phase during replication.

biochemistry↗