PLANT ALLERGENS

Group leader: Araceli Díaz Perales - Professor
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Personnel:

 

Plant Food allergies are an increasing global health concern, affecting millions of individuals and posing serious challenges to food safety. These allergies are primarily caused by plant defense proteins, which can provoke severe immune responses in sensitized individuals. These allergens not only challenge the quality of life of individuals but also have significant implications for food safety. Environmental factors such as climate change can affect the production of allergens in plants, while the introduction of new plant-based foods into diets increases the identification of novel allergens. As a result, the risk to food safety is escalating and must be addressed. Our research group is dedicated to uncovering the molecular mechanism underlying plant-derived food allergies. By combining computational structural biology, molecular biology techniques, and animal models, we aim to provide fundamental insights that support more accurate risk assessment and the development of effective diagnostic and therapeutic tools. (Figure 1).

  


Figure 1. Overview of our multidisciplinary approach to studying plant-based food allergies, combining computational biology, protein characterization, cell cultures, and in vivo research to develop diagnostic and therapeutic solutions.

 

 

Structural Biology and Molecular Characterization of Plant Allergens

Our research begins with an in-depth exploration of plant allergenic proteins to understand their mechanisms of action. One of our studies focuses on the major allergen from Alternaria alternata, Alt a 1, and its interaction with Toll-like receptor 4 (TLR4) (Figure 2). These findings highlight how molecular simulations can provide insights into the mechanisms underlying allergenic responses and help develop more effective diagnostic and therapeutic strategies (doi: 10.3389/fimmu.2022.877383).

  

Figure 2. Interaction between Ala 1 and TLR4. Molecular dynamics simulations. doi: 10.3389/fimmu.2022.877383

 

 

 

 

Another example of our research involves the study of Lipid Transfer Proteins (LTPs), a group of major food allergens. We used molecular dynamics simulations and umbrella sampling techniques to explore the interaction between LTPs and their ligands (Figure 3). Our findings highlight the role of these interactions in promoting allergic sensitization and underscore the importance of protein-ligand dynamics in allergy development (doi:10.1016/j.bbalip.2021.158928)

  

Figure 3. Structure of Pru p 3 and its natural ligand

 

 

 

Molecular Mechanisms of Allergy and Clinical Applications

 

Beyond structural studies, our laboratory focuses on understanding the molecular mechanisms that lead to allergic responses. Our research aims to identify key factors in this process to develop better prevention and treatment strategies for food allergies. Our experiments have shown that when LTPs transport these ligands, they interact with the immune system, triggering allergic responses (Figure 4). (doi:10.1016/j.bbalip.2021.158928; 10.1111/all.15898) This research provides valuable insights into how plant allergens, particularly through the action of their lipid ligands, contribute to the development of food allergies and underscores the importance of studying these interactions for better allergy management and therapeutic development.

  

Figure 4. Comparison of body temperature drop postchallenge in three different allergenic mice model. In three cases the presence of ligand increases drop in temperature. Doi: 10.1111/all.15898

 

 

 

From Discovery to Solutions: Diagnostics and Therapeutics

Finally, all this fundamental knowledge is integrated into the development of practical solutions for food allergy management. In the realm of diagnostics, we design innovative technologies such as portable, multiplexed devices that allow for rapid and accurate allergen detection in food. Projects like AllerScreening (H2020-NMBP-X-KET-2017) and the FOOD-AL Project (FOODAL-CM_P2018/BAAA-4574) aim to provide accessible and efficient allergen detection, improving the ability of both individuals and healthcare providers to manage food allergies effectively.

On the therapeutic front, we are exploring immunotherapy approaches using Virus-Like Particles (VLPs). These plant-derived particles, when combined with allergens such as Pru p 3, have demonstrated promising results in reducing allergic reactions in animal models. Our work on sublingual desensitization therapies has shown that VLPs can reduce allergy markers in mice without causing adverse effects (doi: 10.3389/fimmu.2022.986823). This promising approach highlights the potential of VLP-based therapies in the future treatment of food allergies, offering a safe and effective alternative for managing these increasingly prevalent conditions (doi:10.3390/ijms25137429). (Figure 5)

  

Figure 5. Illustrative diagram of the translational strategies derived from our research. It includes patient diagnosis using multiplex biomarker platforms, rapid allergen detection in food using lateral flow tests, and sublingual immunotherapy with virus-like particles (VLPs) for allergy desensitization.

 

 


Representative Publications

Álvarez, P., Aguado, R., Molina, J., Trujillo-Aguilera, A., Villalba, M., Díaz-Perales, A., Oeo-Santos, C., Chicano, E., Blanco, N., Navas, A., Ruiz-León, B., Jurado, A. 2024. Pollen-Food Allergy Syndrome: From Food Avoidance to Deciphering the Potential Cross-Reactivity between Pru p 3 and Ole e 7. Nutrients 16, 2869. DOI: 10.3390/nu16172869

Berreiros-Hortala, H., Vilchez-Pinto, G., Diaz-Perales, A., Garrido-Arandia, M., Tome-Amat, J. 2024. Virus-like Particles as Vaccines for Allergen-Specific Therapy: An Overview of Current Developments. International Journal of Molecular Sciences 25, 7429. DOI: 10.3390/ijms25137429

Truchado, D.A., Juárez-Molina, M., Rincón, S., Zurita, L., Tomé-Amat, J., Lorz, C., Ponz, F. 2024. A Multifunctionalized Potyvirus-Derived Nanoparticle That Targets and Internalizes into Cancer Cells. International Journal of Molecular Sciences 25, 4327. DOI: 10.3390/ijms25084327

Phelps, A., Pazos-Castro, D., Urselli, F., Grydziuszko, E., Mann-Delany, O., Fang, A., Walker, T.D., Guruge, R.T., Tome-Amat, J., Diaz-Perales, A., Waserman, S., Boonyaratanakornkit, J., Jordana, M., Taylor, J.J., Koenig, J.F.E. 2024. Production and use of antigen tetramers to study antigen-specific B cells. Nature Protocols 1–25. DOI: 10.1038/s41596-023-00930-8

Aguilella, M., Garciadeblás, B., Fernández Pacios, L., Benito, B. 2024. Phylogenetic and Structure-Function Analyses of ENA ATPases: A Case Study of the ENA1 Protein from the Fungus Neurospora crassa. International Journal of Molecular Sciences 25, 514. DOI: 10.3390/ijms25010514

Pacios, L.F., Sánchez, F., Ponz, F. 2024. Intrinsic disorder in the dynamic evolution of structure, stability, and flexibility of potyviral VLP assemblies: A computational study. International Journal of Biological Macromolecules 127798. DOI: 10.1016/j.ijbiomac.2023.127798

Rodríguez, S., García-García, A., Garcia-Calvo, E., Esteban, V., Pastor-Vargas, C., Díaz-Perales, A., García, T., Martín, R. 2023. Generation of an Ovomucoid-Immune scFv Library for the Development of Novel Immunoassays in Hen’s Egg Detection. Foods 12, 3831. DOI: 10.3390/foods12203831

Tome-Amat, J., Gonzalez-Klein, Z., Pazos-Castro, D., Resuela-Gonzalez, J.L., Vilchez-Pinto, G., Berreiros-Hortala, H., Palacio-Garcia, L., Fernandez-Bravo, S., Esteban, V., Diaz-Perales, A., Garrido-Arandia, M. 2023. Plant lipid transfer proteins’ ligand enhances allergic sensitization to non-related proteins in murine models. Allergy. DOI: 10.1111/all.15898

Mínguez-Toral, M., Pacios, L.F., Sánchez, F., Ponz, F. 2023. Structural intrinsic disorder in a functionalized potyviral coat protein as a main viability determinant of its assembled nanoparticles. International Journal of Biological Macromolecules 236, 123958. DOI: 10.1016/j.ijbiomac.2023.123958

Martín-Dacal, M., Fernández-Calvo, P., Jiménez-Sandoval, P., López, G., Garrido-Arandía, M., Rebaque, D., del Hierro, I., Berlanga, D.J., Torres, M.Á., Kumar, V., Mélida, H., Pacios, L.F., Santiago, J., Molina, A. 2022. Arabidopsis immune responses triggered by cellulose and mixed-linked glucan oligosaccharides require a group of Leucine-Rich Repeat-Malectin Receptor Kinases. The Plant Journal. DOI: 10.1111/tpj.16088

Dijk, W., Villa, C., Benedé, S., Vassilopoulou, E., Mafra, I., Garrido-Arandia, M., Martínez Blanco, M., Bouchaud, G., Hoppenbrouwers, T., Bavaro, S.L., Giblin, L., Knipping, K., Castro, A.M., Delgado, S., Costa, J., Bastiaan-Net, S. 2022. Critical features of an in vitro intestinal absorption model to study the first key aspects underlying food allergen sensitization. Comprehensive Reviews in Food Science and Food Safety. DOI: 10.1111/1541-4337.13097

Meile, L., Garrido-Arandia, M., Bernasconi, Z., Peter, J., Schneller, A., Bernasconi, A., Alassimone, J., McDonald, B.A., Sánchez-Vallet, A. 2022. Natural variation in Avr3D1 from Zymoseptoria sp. contributes to quantitative gene-for-gene resistance and to host specificity. New Phytologist. DOI: 10.1111/nph.18690

Regner, A., Szepannek, N., Wiederstein, M., Fakhimahmadi, A., Pacios, L.F., Blokhuis, B.R., Redegeld, F.A., Hofstetter, G., Dvorak, Z., Jensen-Jarolim, E., Hufnagl, K., Roth-Walter, F. 2023. Binding to Iron Quercetin Complexes Increases the Antioxidant Capacity of the Major Birch Pollen Allergen Bet v 1 and Reduces Its Allergenicity. Antioxidants 12, 42. DOI: 10.3390/antiox12010042

Pazos-Castro, D., Margain, C., Gonzalez-Klein, Z., Yuste-Calvo, C., Garrido-Arandia, M., Zurita, L., Esteban, V., Tome-Amat, J., Diaz-Perales, A., Ponz, F. 2022. Suitability of potyviral recombinant virus-like particles bearing a complete food allergen for immunotherapy vaccines. Frontiers in Immunology 13. DOI: 10.3389/fimmu.2022.986823

Murillo, A.M.M., Valle, L.G., Ramírez, Y., Sánchez, M.J., Santamaría, B., Molina-Roldan, E., Ortega-Madueño, I., Urcelay, E., Tramarin, L., Herreros, P., Díaz-Perales, A., Garrido-Arandia, M., Tome-Amat, J., Hernández-Ramírez, G., Espinosa, R.L., Laguna, M.F., Holgado, M. 2022. Integration of Multiple Interferometers in Highly Multiplexed Diagnostic KITs to Evaluate Several Biomarkers of COVID-19 in Serum. Biosensors 12, 671. DOI: 10.3390/bios12090671

Diem, L., Neuherz, B., Rohrhofer, J., Koidl, L., Asero, R., Brockow, K., Diaz Perales, A., Faber, M., Gebhardt, J., Torres, M., Jensen-Jarolim, E., Zehetmayer, S., Untersmayr, E. n.d. Real-life evaluation of molecular multiplex IgE test methods in the diagnosis of pollen associated food allergy. Allergy n/a. DOI: 10.1111/all.15329

Missaoui, K., Gonzalez-Klein, Z., Jemli, S., Garrido-Arandia, M., Diaz-Perales, A., Tome-Amat, J., Brini, F. 2022. Identification and molecular characterization of a novel non-specific lipid transfer protein (TdLTP2) from durum wheat. PLOS ONE 17, e0266971. DOI: 10.1371/journal.pone.0266971

Pali-Schöll, I., Bianchini, R., Afify, S.M., Hofstetter, G., Winkler, S., Ahlers, S., Altemeier, T., Mayerhofer, H., Hufnagl, K., Korath, A.D.J., Pranger, C., Widhalm, R., Hann, S., Wittek, T., Kasper-Giebl, A., Pacios, L.F., Roth-Walter, F., Vercelli, D., von Mutius, E., Jensen-Jarolim, E. 2022. Secretory protein beta-lactoglobulin in cattle stable dust may contribute to the allergy-protective farm effect. Clinical and Translational Allergy 12, e12125. DOI: 10.1002/clt2.12125

Pazos-Castro, D., Gonzalez-Klein, Z., Montalvo, A.Y., Hernandez-Ramirez, G., Romero-Sahagun, A., Esteban, V., Garrido-Arandia, M., Tome-Amat, J., Diaz-Perales, A. 2022. NLRP3 priming due to skin damage precedes LTP allergic sensitization in a mouse model. Scientific Reports 12, 3329. DOI: 10.1038/s41598-022-07421-y

Missaoui, K., Gonzalez-Klein, Z., Pazos-Castro, D., Hernandez-Ramirez, G., Garrido-Arandia, M., Brini, F., Diaz-Perales, A., Tome-Amat, J. 2022. Plant non-specific lipid transfer proteins: An overview. Plant Physiology and Biochemistry 171, 115–127. DOI: 10.1016/j.plaphy.2021.12.026

Hernandez-Ramirez, G., Barber, D., Tome-Amat, J., Garrido-Arandia, M., Diaz-Perales, A. 2021. Alternaria as an Inducer of Allergic Sensitization. Journal of Fungi 7, 838. DOI: 10.3390/jof7100838

Phillips, A.H., Hernandez, J.A., Payá-Tormo, L., Burén, S., Cuevas-Zuviría, B., Pacios, L.F., Pelton, J.G., Wemmer, D.E., Rubio, L.M. 2021. Environment and coordination of FeMo–co in the nitrogenase metallochaperone NafY. RSC Chemical Biology. DOI: 10.1039/D1CB00086A

Murillo, A.M.M., Tomé-Amat, J., Ramírez, Y., Garrido-Arandia, M., Valle, L.G., Hernández-Ramírez, G., Tramarin, L., Herreros, P., Santamaría, B., Díaz-Perales, A., Holgado, M. 2021. Developing an optical interferometric detection method based biosensor for the detection of detecting specific SARS-CoV-2 immunoglobulins in serum and saliva, and their corresponding ELISA correlation. Sensors and Actuators B: Chemical 130394. DOI: 10.1016/j.snb.2021.130394

Skypala, I.J., Asero, R., Barber, D., Cecchi, L., Diaz-Perales, A., Hoffmann-Sommergruber, K., Pastorello, E.A., Swoboda, I., Bartra, J., Ebo, D.G., Faber, M.A., Fernández-Rivas, M., Gomez, F., Konstantinopoulos, A.P., Luengo, O., Ree, R. van, Scala, E., Till, S.J. 2021. Non-specific lipid-transfer proteins: Allergen structure and function, cross-reactivity, sensitization, and epidemiology. Clinical and Translational Allergy 11, e12010. DOI: 10.1002/clt2.12010

Gonzalez-Klein, Z., Cuevas-Zuviria, B., Wangorsch, A., Hernandez-Ramirez, G., Pazos-Castro, D., Oeo-Santos, C., Romero-Sahagun, A., Pacios, L.F., Tome-Amat, J., Scheurer, S., Diaz-Perales, A., Garrido-Arandia, M. 2021. The key to the allergenicity of lipid transfer protein (LTP) ligands: A structural characterization. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1866, 158928. DOI: 10.1016/j.bbalip.2021.158928

Cuevas-Zuviría, B., Pacios, L.F. 2021. Machine Learning of Analytical Electron Density in Large Molecules Through Message-Passing. Journal of Chemical Information and Modeling. DOI: 10.1021/acs.jcim.1c00227

Skypala, I.J., Bartra, J., Ebo, D.G., Faber, M.A., Fernández‐Rivas, M., Gomez, F., Luengo, O., Till, S.J., Asero, R., Barber, D., Cecchi, L., Diaz-Perales, A., Hoffmann‐Sommergruber, K., Pastorello, E.A., Swoboda, I., Konstantinopoulos, A.P., Ree, R. van, Scala, E. 2021. The diagnosis and management of allergic reactions in patients sensitized to non-specific Lipid Transfer Proteins. Allergy. DOI: https://doi.org/10.1111/all.14797

Costa, J., Villa, C., Verhoeckx, K., Cirkovic-Velickovic, T., Schrama, D., Roncada, P., Rodrigues, P.M., Piras, C., Martín-Pedraza, L., Monaci, L., Molina, E., Mazzucchelli, G., Mafra, I., Lupi, R., Lozano-Ojalvo, D., Larré, C., Klueber, J., Gelencser, E., Bueno-Diaz, C., Diaz-Perales, A., Benedé, S., Bavaro, S.L., Kuehn, A., Hoffmann-Sommergruber, K., Holzhauser, T. 2021. Are Physicochemical Properties Shaping the Allergenic Potency of Animal Allergens?. Clinical Reviews in Allergy & Immunology. DOI: 10.1007/s12016-020-08826-1

Espinosa, R.L., Garrido-Arandia, M., Romero-Sahagun, A., Herreros, P., Tramarin, L., Laguna, M.F., Díaz-Perales, A., Holgado, M. 2020. A new optical interferometric-based in vitro detection system for the specific IgE detection in serum of the main peach allergen. Biosensors and Bioelectronics 169, 112641. DOI: 10.1016/j.bios.2020.112641

Costa, J., Bavaro, S.L., Benedé, S., Diaz-Perales, A., Bueno-Diaz, C., Gelencser, E., Klueber, J., Larré, C., Lozano-Ojalvo, D., Lupi, R., Mafra, I., Mazzucchelli, G., Molina, E., Monaci, L., Martín-Pedraza, L., Piras, C., Rodrigues, P.M., Roncada, P., Schrama, D., Cirkovic-Velickovic, T., Verhoeckx, K., Villa, C., Kuehn, A., Hoffmann-Sommergruber, K., Holzhauser, T. 2020. Are Physicochemical Properties Shaping the Allergenic Potency of Plant Allergens?. Clinical Reviews in Allergy & Immunology. DOI: 10.1007/s12016-020-08810-9

Cuevas-Zuviría, B., Pacios, L.F. 2020. Analytical Model of Electron Density and Its Machine Learning Inference. Journal of Chemical Information and Modeling 60, 3831–3842. DOI: 10.1021/acs.jcim.0c00197

Mínguez-Toral, M., Cuevas-Zuviría, B., Garrido-Arandia, M., Pacios, L.F. 2020. A computational structural study on the DNA-protecting role of the tardigrade-unique Dsup protein. Scientific Reports 10, 13424. DOI: 10.1038/s41598-020-70431-1

López‐González, S., Navarro, J.A., Pacios, L.F., Sardaru, P., Pallás, V., Sánchez, F., Ponz, F. 2020. Association between flower stalk elongation, an Arabidopsis developmental trait, and the subcellular location and movement dynamics of the nonstructural protein P3 of Turnip mosaic virus. Molecular Plant Pathology. DOI: 10.1111/mpp.12976

Roth-Walter, F., Afify, S.M., Pacios, L.F., Blokhuis, B.R., Redegeld, F., Regner, A., Petje, L.-M., Fiocchi, A., Untersmayr, E., Dvorak, Z., Hufnagl, K., Pali-Schöll, I., Jensen-Jarolim, E. 2020. Cow’s milk protein β-lactoglobulin confers resilience against allergy by targeting complexed iron into immune cells. Journal of Allergy and Clinical Immunology. DOI: 10.1016/j.jaci.2020.05.023

Hernández‐Ramírez, G., Pazos‐Castro, D., Torrijos, E.G., Montalvo, A.Y., Romero‐Sahagun, A., González‐Klein, Z., Jimeno‐Nogales, L., Escribese, M.M., Ortega, A.E., Nuñez‐Borque, E., Orvay, L.B., Esteban, V., Brito, F.F., Barber, D., Tome‐Amat, J., Garrido‐Arandia, M., Díaz‐Perales, A. 2020. Group 1 allergens, transported by mold spores, induce asthma exacerbation in a mouse model. Allergy. DOI: 10.1111/all.14347

Cuevas-Zuviría, B., Mínguez-Toral, M., Díaz-Perales, A., Garrido-Arandia, M., Pacios, L.F. 2020. Structural Dynamics of the Lipid Antigen-Binding Site of CD1d Protein. Biomolecules 10, 532. DOI: 10.3390/biom10040532

Cuevas-Zuviría, B., Mínguez-Toral, M., Díaz-Perales, A., Garrido-Arandia, M., Pacios, L.F. 2020. Dynamic plasticity of the lipid antigen-binding site of CD1d is crucially favoured by acidic pH and helper proteins. Scientific Reports 10, 5714. DOI: 10.1038/s41598-020-62833-y

Blanca, M., Puche, L.V., Garrido-Arandia, M., Martin-Pedraza, L., Sahagún, A.R., López-Sánchez, J.D., Galán, C., Marin, A., Villaba, M., Díaz-Perales, A., Somoza, M.L. 2020. Pru p 9, a new allergen eliciting respiratory symptoms in subjects sensitized to peach tree pollen. PLOS ONE 15, e0230010. DOI: 10.1371/journal.pone.0230010

Orozco-Navarrete, B., Kaczmarska, Z., Dupeux, F., Garrido-Arandia, M., Pott, D., Díaz-Perales, A., Casañal, A., Márquez, J.A., Valpuesta, V., Merchante, C. 2019. Structural Bases for the Allergenicity of Fra a 1.02 in Strawberry Fruits. Journal of Agricultural and Food Chemistry. DOI: 10.1021/acs.jafc.9b05714

Oeo‐Santos, C., Navas, A., Benedé, S., Ruíz‐León, B., Díaz‐Perales, A., Vogel, L., Moreno‐Aguilar, C., Jurado, A., Villalba, M., Barderas, R. 2019. New insights into the sensitization to non-related nsLTPs from pollen and food: new role of the allergen Ole e 7. Allergy. DOI: 10.1111/all.14086

Victorio Puche, L., Somoza, M.L., López-Sánchez, J.D., Garrido-Arandia, M., Díaz-Perales, A., Blanca, M. 2019. Peach Tree Pollen and Prunus persica 9 Sensitisation and Allergy in Children and Adolescents. International Archives of Allergy and Immunology 180, 212–220. DOI: 10.1159/000502352

Delgado, R., Abad-Guamán, R., Nicodemus, N., Diaz-Perales, A., García, J., Carabaño, R., Menoyo, D. 2019. Effect of pre- and post-weaning dietary supplementation with arginine and glutamine on rabbit performance and intestinal health. BMC Veterinary Research 15, 199. DOI: 10.1186/s12917-019-1945-2

Garrido‐Arandia, M., Tome‐Amat, J., Pazos‐Castro, D., Esteban, V., Escribese, M.M., Hernández‐Ramírez, G., Yuste, A.M., Barber, D., Pacios, L.F., Díaz‐Perales, A. 2019. Interaction of Alt a 1 with SLC22A17 in the airway mucosa. Allergy. DOI: 10.1111/all.13877

Somoza, M.L., Garrido‐Arandia, M., Victorio, L., López‐Sánchez, J.D., Blanca‐López, N., Haroun‐Diaz, E., Sahagún, A.R., Díaz‐Perales, A., Canto, G., Blanca, M. 2019. Peach tree pollen and Pru p 9 may induce rhinoconjunctivitis and asthma in children. Pediatric Allergy and Immunology. DOI: 10.1111/pai.13067

Yuste-Calvo, C., González-Gamboa, I., Pacios, L.F., Sánchez, F., Ponz, F. 2019. Structure-Based Multifunctionalization of Flexuous Elongated Viral Nanoparticles. ACS Omega 4, 5019–5028. DOI: 10.1021/acsomega.8b02760

Cuevas-Zuviría, B., Garrido-Arandia, M., Díaz-Perales, A., Pacios, L.F. 2019. Energy Landscapes of Ligand Motion Inside the Tunnel-Like Cavity of Lipid Transfer Proteins: The Case of the Pru p 3 Allergen. International Journal of Molecular Sciences 20, 1432. DOI: 10.3390/ijms20061432

Lozano-Ojalvo, D., Benedé, S., Antunes, C.M., Bavaro, S.L., Bouchaud, G., Costa, A., Denery-Papini, S., Díaz-Perales, A., Garrido-Arandia, M., Gavrovic-Jankulovic, M., Hayen, S., Martínez-Blanco, M., Molina, E., Monaci, L., Pieters, R.H.H., Villemin, C., Wichers, H.J., Wróblewska, B., Willemsen, L.E.M., Roggen, E.L., van Bilsen, J.H.M. 2019. Applying the adverse outcome pathway (AOP) for food sensitization to support in vitro testing strategies. Trends in Food Science & Technology 85, 307–319. DOI: 10.1016/j.tifs.2019.01.014

Albareda, M., Pacios, L.F., Palacios, J.M. 2019. Computational analyses, molecular dynamics, and mutagenesis studies of unprocessed form of [NiFe] hydrogenase reveal the role of disorder for efficient enzyme maturation. Biochimica et Biophysica Acta (BBA) - Bioenergetics 1860, 325–340. DOI: 10.1016/j.bbabio.2019.01.001