| Summary: | <i>Paracoccidioides</i> spp. are endemic fungi from Latin America that cause Paracoccidioidomycosis, a systemic disease. These fungi present systems for high-affinity metal uptake, storage, and mobilization, which counteract host nutritional immunity and mitigate the toxic effects of metals. Regarding Cu mobilization, the metallochaperone Atx1 is regulated according to Cu bioavailability in <i>Paracoccidioides</i> spp., contributing to metal homeostasis. However, additional information in the literature on <i>Pb</i>Atx1 is scarce. Therefore, in the present work, we aimed to study the <i>Pb</i>Atx1 protein–protein interaction networks. Heterologous expressed <i>Pb</i>Atx1 was used in a pull-down assay with <i>Paracoccidioides brasiliensis</i> cytoplasmic extract. Nineteen proteins that interacted with <i>Pb</i>Atx1 were identified by HPLC-MS<sup>E</sup>. Among them, a relevant finding was a Cytochrome <i>b</i><sub>5</sub> (<i>Pb</i>Cyb5), regulated by Fe bioavailability in <i>Aspergillus fumigatus</i> and highly secreted by <i>P. brasiliensis</i> in Fe deprivation. We validated the interaction between <i>Pb</i>Atx1-<i>Pb</i>Cyb5 through molecular modeling and far-Western analyses. It is known that there is a relationship between Fe homeostasis and Cu homeostasis in organisms. In this sense, would <i>Pb</i>Atx1-<i>Pb</i>Cyb5 interaction be a new metal-sensor system? Would it be supported by the presence/absence of metals? We intend to answer those questions in future works to contribute to the understanding of the strategies employed by <i>Paracoccidioides</i> spp. to overcome host defenses.
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