Biology subjects

Pullin, J.

Publications and source records attributed to Pullin, J..

3 recordsLinked to original sources

bioRxiv2025

Human mitochondrial ferritin exhibits highly unusual iron-O2 chemistry distinct from that of cytosolic ferritins

Ferritins are ubiquitous proteins that function in iron storage and detoxification. Mammalian tissues that are metabolically highly active contain, in addition to the ubiquitous cytosolic ferritin, a ferritin that is localised to mitochondria. Mitochondrial ferritin (FtMt) functions to protect against oxidative stress and is found at higher levels in disease states that are associated with abnormal iron accumulation, such as Alzheimers and Parkinsons. Here we demonstrate that, despite 80% sequence identity with cytosolic human H-chain ferritin, Fe2+ oxidation at the catalytic diiron ferroxidase centre of FtMt proceeds via a distinct mechanism involving radical formation on a strictly conserved Tyr residue (Tyr34), and a mixed-valent ferroxidase centre (MVFC) that is readily detected under the O2-limiting conditions typical of mitochondria. Tyr34 is key for the activation of O2 and stability of the MVFC. The highly unusual iron-O2 chemistry exhibited by FtMt demonstrates that high levels of sequence identity between enzymes does not guarantee similarity of catalytic mechanism; here we explore the possible origin of the mechanistic differences between FtMt and cytosolic human H-chain ferritin.

biochemistry↗

bioRxiv2024

Polymorphic tandem repeats shape single-cell gene expression across the immune landscape

Tandem repeats (TRs) - highly polymorphic, repetitive sequences across the human genome - are important regulators of gene expression but remain underexplored due to challenges in accurate genotyping and analysis1. Here, we generate new whole genome and single-cell RNA sequencing from >5.4 million blood-derived cells across 1,925 individuals in two cohorts [Cuomo et al., accompanying manuscript], and perform meta-analysis to characterize the impact of variation in >1.7 million TR loci on immune cell type-specific gene expression. We identify >69,000 single-cell expression TR loci (sc-eTRs), 30.7% of which are specific to one of 28 immune cell types, and reveal dynamic regulatory effects using cell-state inference. Matched single-cell ATAC sequencing profiles from >3.4 million nuclei in 922 individuals [Xue et al., accompanying manuscript]. uncover chromatin accessibility QTLs for nearly one-third of expression-associated TRs, supporting coordinated effects on cis-regulatory architecture. Fine-mapping implicates 1,490 TRs as candidate causal drivers of gene expression in 6.1% of tested genes, and colocalization analyses highlight >200 genes in which TRs likely mediate genetic associations with immune and hematological traits. Together, these results provide a genome-wide, multiomic view of TR-mediated regulation in the human immune system, establishing TRs as key contributors to cell type-specific regulatory variation and complex trait architecture.

genomics↗

bioRxiv2024

Iron and redox sensing in plants: properties of the hemerythrin-like domains of Arabidopsis BRUTUS and BRUTUS-LIKE2 proteins

Iron uptake in plants is negatively regulated by highly conserved hemerythrin (Hr) E3 ubiquitin ligases exemplified by Arabidopsis thaliana BRUTUS (BTS). Physiological studies suggest these are the elusive plant iron sensors, but biochemical evidence is lacking. Here we demonstrate that the N-terminal domains of BTS and BTS-LIKE2 (BTSL2) respectively bind three and two diiron centres within three closely packed Hr-like subdomains. The centres can be reversibly oxidized by O2 and H2O2, resulting in a di-Fe3+ form that is non-labile. In the reduced state, a proportion of the iron becomes labile, based on accessibility to Fe2+ chelators and reconstitution experiments, consistent with dynamic iron binding. Impaired iron binding and altered redox properties in the BTS dgl variant correlate with diminished capacity to suppress the downstream signalling cascade. These data provide the biochemical foundation for a mechanistic model of how BTS/Ls function as iron sensors that are unique to the plant kingdom.

biochemistry↗