Biology subjects

Fissore, A.

Publications and source records attributed to Fissore, A..

3 recordsLinked to original sources

bioRxiv2025

Dissecting Annexin-A11 into its functional domains revealed calcium as a key regulator for RNA transport and its association with ALS

Recent studies reveal a "hitchhiking" mechanism in neurons, where organelles transported along microtubules carry other cargos via tethering molecules. Annexin A11 (ANXA11), a calcium-dependent phospholipid-binding protein, functions as a tether linking RNA granules to lysosomes, aiding mRNA transport for rapid neuronal responses. Structurally, its N-terminal (Nt) binds RNA, while the C-terminal (Ct) associates with lysosomal membranes. Mutations in ANXA11 linked to Amyotrophic lateral sclerosis (ALS) may disrupt this function. Here, applying a multidisciplinary approach, we revealed that Ca2+ acts as a master regulator of ANXAlls physiological function by modulating its conformational states. Specifically, Ca2+ influences a switch between two conformations: a close state, in which the Nt and Ct interact with each other, and an open state, which occurs in the presence of Ca2+ ions, where this self-interaction is disrupted, allowing the two domains to interact freely with RNA and liposomes. Surprisingly, we observed that both the Ct and Nt are capable of interacting with liposomes and RNA in a Ca2+-dependent manner, and these interactions can occur simultaneously. This dual binding and its calcium-regulated hierarchy finely tunes ANXAlls binding to RNA and lysosomes, promoting a large complex essential for overcoming transport steric hindrance. Moreover, our result showed that the p.D40G mutation, in the Nt domain, associated with ALS, displays destabilized interdomain interactions and bypass Ca2+ regulation, leading to aberrant aggregation. These insights advance our understanding of ANXAlls role in neuronal RNA transport and its disruption in neurodegeneration, highlighting potential targets for therapeutic intervention.

biochemistry↗

bioRxiv2025

Characterization of Mycobacterium tuberculosis rhodanese-like sulfurtransferase SseA and its newly identified activator Rv3284: A new pathway to exploit as a drug target?

Tuberculosis (TB) remains a critical global health challenge, with Mycobacterium tuberculosis (Mtb) causing 10.8 million cases and 1.25 million deaths in 2023. Key issues include the dormant state of Mtb, resistant to drugs and immune responses, and the emergence of multi-drug-resistant strains. This underscores the need for new therapeutic targets and deeper research into Mtb pathogenesis and immunology. A potential drug target is the enzyme thiosulfate-sulfurtransferase SseA, which plays a role in macrophage infection by Mtb and its resistance to oxidative stress. SseA belongs to the rhodanese-like enzyme family, which catalyzes sulfur transfer reactions essential for Mtb survival. In our research, we identified a new protein (Rv3284), hereinafter referred to as SufEMtb due to its high homology with E. coli SufE, that interacts with SseA and modulates its activity. Sequence analysis and AI molecular modelling revealed detailed insights into their interaction that can contribute to the modulation of SseA activity. This research provides a mechanistic explanation to the need of a partner for SseA activation. Indeed, we propose that SufEMtb enhances SseA enzymatic function by binding to its non-catalytic N-terminal domain and bringing the active sites of the two proteins in close proximity, thus preparing for the activation-enhancing conformational change in a regulatory loop of SseA. This interaction is crucial for the effective enzyme activity and the maintenance of redox homeostasis in Mtb, making the SseA-SufEMtb protein complex a potential target for new TB therapies.

biochemistry↗

bioRxiv2024

Corylus avellana non-specific lipid-transfer protein Cor a 8 is a moonlighting enzyme with a new lipase activity

The high-fat content of hazelnuts, mainly triglycerides, makes them prone to lipid oxidation during storage, which has a big impact on their sensory and nutritional quality. The chemical pathways leading to hazelnut oxidative rancidity have been well characterized and it are faster on free fatty acids. Lipase(s) enzymes are required, in oilseed, to hydrolyze the ester bond to free the single molecule of fatty acids. This step, necessary for germination, is the first event to trigger rancidity. Identifying the lipase(s) enzyme and the biochemical pathways involved in rancidity would lead to an effective strategy to prevent fat deterioration. Different proteins have been characterized in hazelnut seed and great interest has been risen towards the non-specific lipid transfer protein family because they were identified as human allergens. Here we show that Cor a 8 - a member of nsLTP - is a novel non-regiospecific lipase that is able to bind to oil-water interfaces and hydrolyze the triacylglycerol (TAGs) ester bonds by a non-canonical active site (non-serine dependent). Molecular modelling and molecular dynamics suggest that Cor a 8 is a moonlighting enzyme not only able to catalyze the hydrolysis of TAGs but also to stabilize the resulting free fatty acids and transport it. Cor a 8 homologues are present in all land plants, but the specific catalytic amino acids are found only in angiosperms, suggesting an evolutionary adaptation for lipid metabolism unique to flowering plants. This study sets the foundation for understanding this new lipid metabolism in plants and its role in rancidity development.

biochemistry↗