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      The role of the Mediator complex in fungal pathogenesis and response to antifungal agents

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          Abstract

          Mediator is a complex of polypeptides that plays a central role in the recruitment of RNA polymerase II to promoters and subsequent transcriptional activation in eukaryotic organisms. Studies have now shown that Mediator has a role in regulating expression of genes implicated in virulence and antifungal drug resistance in pathogenic fungi. The roles of specific Mediator subunits have been investigated in several species of pathogenic fungi, particularly in the most pathogenic yeast Candida albicans. Uniquely, pathogenic yeast also present several interesting examples of divergence in Mediator structure and function, most notably in C. glabrata, which possesses two orthologues of Med15, and in C. albicans, which has a massively expanded family of Med2 orthologues known as the TLO gene family. This review highlights specific examples of recent progress in characterizing the role of Mediator in pathogenic fungi.

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          Highly accurate protein structure prediction with AlphaFold

          Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort 1 – 4 , the structures of around 100,000 unique proteins have been determined 5 , but this represents a small fraction of the billions of known protein sequences 6 , 7 . Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence—the structure prediction component of the ‘protein folding problem’ 8 —has been an important open research problem for more than 50 years 9 . Despite recent progress 10 – 14 , existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14) 15 , demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm. AlphaFold predicts protein structures with an accuracy competitive with experimental structures in the majority of cases using a novel deep learning architecture.
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            AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models

            The AlphaFold Protein Structure Database (AlphaFold DB, https://alphafold.ebi.ac.uk ) is an openly accessible, extensive database of high-accuracy protein-structure predictions. Powered by AlphaFold v2.0 of DeepMind, it has enabled an unprecedented expansion of the structural coverage of the known protein-sequence space. AlphaFold DB provides programmatic access to and interactive visualization of predicted atomic coordinates, per-residue and pairwise model-confidence estimates and predicted aligned errors. The initial release of AlphaFold DB contains over 360,000 predicted structures across 21 model-organism proteomes, which will soon be expanded to cover most of the (over 100 million) representative sequences from the UniRef90 data set.
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              Global and Multi-National Prevalence of Fungal Diseases—Estimate Precision

              Fungal diseases kill more than 1.5 million and affect over a billion people. However, they are still a neglected topic by public health authorities even though most deaths from fungal diseases are avoidable. Serious fungal infections occur as a consequence of other health problems including asthma, AIDS, cancer, organ transplantation and corticosteroid therapies. Early accurate diagnosis allows prompt antifungal therapy; however this is often delayed or unavailable leading to death, serious chronic illness or blindness. Recent global estimates have found 3,000,000 cases of chronic pulmonary aspergillosis, ~223,100 cases of cryptococcal meningitis complicating HIV/AIDS, ~700,000 cases of invasive candidiasis, ~500,000 cases of Pneumocystis jirovecii pneumonia, ~250,000 cases of invasive aspergillosis, ~100,000 cases of disseminated histoplasmosis, over 10,000,000 cases of fungal asthma and ~1,000,000 cases of fungal keratitis occur annually. Since 2013, the Leading International Fungal Education (LIFE) portal has facilitated the estimation of the burden of serious fungal infections country by country for over 5.7 billion people (>80% of the world’s population). These studies have shown differences in the global burden between countries, within regions of the same country and between at risk populations. Here we interrogate the accuracy of these fungal infection burden estimates in the 43 published papers within the LIFE initiative.
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                Author and article information

                Contributors
                Journal
                Essays Biochem
                Essays Biochem
                ebc
                Essays in Biochemistry
                Portland Press Ltd.
                0071-1365
                1744-1358
                September 2023
                13 September 2023
                : 67
                : 5 , Fungal Biochemistry
                : 843-851
                Affiliations
                Microbiology Research Unit, Division of Oral Biosciences, Dublin Dental University Hospital, University of Dublin, Trinity College Dublin, Dublin, Ireland
                Author notes
                Correspondence: Gary P. Moran ( gmoran@ 123456tcd.ie )
                [*]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-0469-1788
                Article
                EBC20220238
                10.1042/EBC20220238
                10500203
                37013399
                edf759e5-57b0-4409-87c3-eac6c564d835
                © 2023 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 27 January 2023
                : 15 March 2023
                : 17 March 2023
                Page count
                Pages: 9
                Categories
                Microbiology
                Gene Expression & Regulation
                Host-Microbe Interactions
                Review Articles

                drug resistance,fungi,mediator,pathogenic,virulence,yeast
                drug resistance, fungi, mediator, pathogenic, virulence, yeast

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