Role of misfolding in rare enzymatic deficits and use of pharmacological chaperones as therapeutic approach

Gioena Pampalone; Silvia Grottelli; Leonardo Gatticchi; Emilia Maria Lombardi; Ilaria Bellezza; Barbara Cellini

doi:10.52586/5056

journal article Open Access Dec 30, 2021

Role of misfolding in rare enzymatic deficits and use of pharmacological chaperones as therapeutic approach

Gioena Pampalone Silvia Grottelli Leonardo Gatticchi Emilia Maria Lombardi Ilaria Bellezza

Barbara Cellini

Frontiers in Bioscience-Landmark Vol. 26 No. 12 · IMR Press

View at Publisher Save 10.52586/5056

Abstract

Cells have evolved sophisticated molecular control systems to maximize the efficiency of the folding process. However, any subtle alteration of the environment or the protein can lead to misfolding or affect the conformational plasticity of the native states. It has been widely demonstrated that misfolding and/or conformational instability are the underlying mechanisms of several rare disorders caused by enzymatic deficits. In fact, disease-causing mutations often lead to the substitution of amino acids that are crucial for the achievement of a folded conformation, or play a role on the equilibrium between native-state conformers. One of the promising approaches to treat conformational disorders is the use of pharmacological chaperones (PCs), small molecules that specifically bind a target protein and stabilize a functional fold, thus increasing the amount of functionally active enzyme. Molecules acting as PCs are usually coenzymes, substrate analogues behaving as competitive inhibitors, or allosteric modulators. In this review, the general features of PCs are described, along with three examples of diseases (Gaucher disease, Phenylketonuria, and Primary Hyperoxaluria) in which this approach is currently under study at preclinical and/or clinical level.

Topics

No keywords indexed for this article. Browse by subject →

References

176

[1]

Nassar R, Dignon GL, Razban RM, Dill KA. The Protein Folding Problem: the Role of Theory. Journal of Molecular Biology. 2021; 433: 167126. 10.1016/j.jmb.2021.167126

[2]

Principles that Govern the Folding of Protein Chains

Christian B. Anfinsen

Science 10.1126/science.181.4096.223

[3]

Hingorani KS, Gierasch LM. Comparing protein folding in vitro and in vivo: foldability meets the fitness challenge. Current Opinion in Structural Biology. 2014; 24: 81–90. 10.1016/j.sbi.2013.11.007

[4]

Mallamace F, Corsaro C, Mallamace D, Vasi S, Vasi C, Baglioni P, et al. Energy landscape in protein folding and unfolding. Proceedings of the National Academy of Sciences of the United States of America. 2016; 113: 3159–3163. 10.1073/pnas.1524864113

[5]

Stollar EJ, Smith DP. Uncovering protein structure. Essays in Biochemistry. 2020; 64: 649–680. 10.1042/ebc20190042

[6]

Muñoz V, Cerminara M. When fast is better: protein folding fundamentals and mechanisms from ultrafast approaches. Biochemical Journal. 2016; 473: 2545–2559. 10.1042/bcj20160107

[7]

From Levinthal to pathways to funnels

Ken A. Dill, Hue Sun Chan

Nature Structural & Molecular Biology 10.1038/nsb0197-10

[8]

Protein folding funnels: the nature of the transition state ensemble

José Nelson Onuchic, Nicholas D. Socci, Zaida Luthey-Schulten et al.

Folding and Design 10.1016/s1359-0278(96)00060-0

[9]

Ivankov DN, Finkelstein A V. Solution of Levinthal’s Paradox and a Physical Theory of Protein Folding Times. Biomolecules. 2020; 10: 250. 10.3390/biom10020250

[10]

Malhotra P, Udgaonkar JB. How cooperative are protein folding and unfolding transitions? Protein Science. 2016; 25: 1924–1941. 10.1002/pro.3015

[11]

The nature of protein folding pathways

S. Walter Englander, Leland Mayne

Proceedings of the National Academy of Sciences 10.1073/pnas.1411798111

[12]

Mannini B, Chiti F. Chaperones as Suppressors of Protein Misfolded Oligomer Toxicity. Frontiers in Molecular Neuroscience. 2017; 10: 98. 10.3389/fnmol.2017.00098

[13]

Chong S, Im H, Ham S. Explicit Characterization of the Free Energy Landscape of pKID-KIX Coupled Folding and Binding. American Chemical Society Central Science. 2019; 5: 1342–1351. 10.1021/acscentsci.9b00200

[14]

Kuwajima K. The Molten Globule, and Two-State vs. Non-Two-State Folding of Globular Proteins. Biomolecules. 2020; 10: 407. 10.3390/biom10030407

[15]

Fast-folding eriments and the topography of protein folding energy landscapes

P G Wolynes, Z. Luthey-Schulten, J.N. Onuchic

Chemistry & Biology 10.1016/s1074-5521(96)90090-3

[16]

Protein folding and misfolding

Christopher M. Dobson

Nature 10.1038/nature02261

[17]

Wang J, Oliveira RJ, Chu X, Whitford PC, Chahine J, Han W, et al. Topography of funneled landscapes determines the thermodynamics and kinetics of protein folding. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109: 15763–15768. 10.1073/pnas.1212842109

[18]

Bemporad F, Chiti F. “Native-like aggregation” of the acylphosphatase from Sulfolobus solfataricus and its biological implications. Federation of European Biochemical Societies. 2009; 583: 2630–2638. 10.1016/j.febslet.2009.07.013

[19]

Uversky VN. Protein intrinsic disorder and structure-function continuum. Progress in Molecular Biology and Translational Science. 2019; 8: 1–17. 10.1016/bs.pmbts.2019.05.003

[20]

Gianni S, Freiberger MI, Jemth P, Ferreiro DU, Wolynes PG, Fuxreiter M. Fuzziness and Frustration in the Energy Landscape of Protein Folding, Function, and Assembly. Accounts of Chemical Research. 2021; 54: 1251–1259. 10.1021/acs.accounts.0c00813

[21]

Zhang Z, Witham S, Alexov E. On the role of electrostatics in protein-protein interactions. Physical Biology. 2011; 8: 035001. 10.1088/1478-3975/8/3/035001

[22]

Chiti F, Dobson CM. Protein Misfolding, Amyloid Formation, and Human Disease: a Summary of Progress over the last Decade. Annual Review of Biochemistry. 2017; 86: 27–68. 10.1146/annurev-biochem-061516-045115

[23]

Uyar B, Weatheritt RJ, Dinkel H, Davey NE, Gibson TJ. Proteome-wide analysis of human disease mutations in short linear motifs: neglected players in cancer? Molecular BioSystems. 2014; 10: 2626–2642. 10.1039/c4mb00290c

[24]

Classification of Intrinsically Disordered Regions and Proteins

Robin van der Lee, Marija Buljan, Benjamin Lang et al.

Chemical Reviews 10.1021/cr400525m

[25]

Singh N, Bhalla N. Moonlighting Proteins. Annual Review of Genetics. 2020; 54: 265–285. 10.1146/annurev-genet-030620-102906

[26]

Li W, Kinch LN, Karplus PA, Grishin NV. ChSeq: a database of chameleon sequences. Protein Science. 2015; 24: 1075–1086. 10.1002/pro.2689

[27]

Jaffe EK. Morpheeins–a new structural paradigm for allosteric regulation. Trends in Biochemical Sciences. 2005; 30: 490–497. 10.1016/j.tibs.2005.07.003

[28]

Dishman AF, Volkman BF. Unfolding the Mysteries of Protein Metamorphosis. American Chemical Society Chemical Biology. 2018; 13: 1438–1446. 10.1021/acschembio.8b00276

[29]

Liu H, Jeffery CJ. Moonlighting Proteins in the Fuzzy Logic of Cellular Metabolism. Molecules. 2020; 25: 3440. 10.3390/molecules25153440

[30]

McDonald S, Murphy T, Imberti S, Warr GG, Atkin R. Amphiphilically Nanostructured Deep Eutectic Solvents. The Journal of Physical Chemistry Letters. 2018; 9: 3922–3927. 10.1021/acs.jpclett.8b01720

[31]

In vivo aspects of protein folding and quality control

David Balchin, Manajit Hayer-Hartl, F. Ulrich Hartl

Science 10.1126/science.aac4354

[32]

Weis BL, Schleiff E, Zerges W. Protein targeting to subcellular organelles via MRNA localization. Biochimica et Biophysica Acta. 2013; 1833: 260–273. 10.1016/j.bbamcr.2012.04.004

[33]

Cheung MS, Arcus V. Editorial overview: Protein folding and binding: from protein folding in vitro to hierarchical assembly in vivo. Current Opinion in Structural Biology. 2021; 66: vi–vii. 10.1016/j.sbi.2021.01.009

[34]

Gámez A, Yuste-Checa P, Brasil S, Briso-Montiano Á, Desviat LR, Ugarte M, et al. Protein misfolding diseases: Prospects of pharmacological treatment. Clinical Genetics. 2018; 93: 450–458. 10.1111/cge.13088

[35]

Protein quality control in the secretory pathway

Zhihao Sun, Jeffrey L. Brodsky

The Journal of cell biology 10.1083/jcb.201906047

[36]

The Biology of Proteostasis in Aging and Disease

Johnathan Labbadia, Richard I Morimoto

Annual Review of Biochemistry 10.1146/annurev-biochem-060614-033955

[37]

Dong Z, Cui H. The Autophagy-Lysosomal Pathways and Their Emerging Roles in Modulating Proteostasis in Tumors. Cells. 2018; 8: 4. 10.3390/cells8010004

[38]

Barrio R, Sutherland JD. Proteostasis: the network behind the networks. Seminars in Cell & Developmental Biology. 2019; 93: 97–99. 10.1016/j.semcdb.2019.04.011

[39]

Dobson CM. Principles of protein folding, misfolding and aggregation. Seminars in Cell & Developmental Biology. 2004; 15: 3–16. 10.1016/j.semcdb.2003.12.008

[40]

Rodríguez-Bolaños M, Miranda-Astudillo H, Pérez-Castañeda E, González-Halphen D, Perez-Montfort R. Native aggregation is a common feature among triosephosphate isomerases of different species. Scientific Reports. 2020; 10: 1338. 10.1038/s41598-020-58272-4

[41]

Bemporad F, De Simone A, Chiti F, Dobson C. Characterizing Intermolecular Interactions that Initiate Native-Like Protein Aggregation. Biophysical Journal. 2012; 102: 2595–2604. 10.1016/j.bpj.2012.03.057

[42]

Jeffery CJ. Protein moonlighting: what is it, and why is it important? Philosophical Transactions of the Royal Society B: Biological Sciences. 2018; 373: 20160523. 10.1098/rstb.2016.0523

[43]

Jaffe EK, Stith L. ALAD porphyria is a conformational disease. American Journal of Human Genetics. 2007; 80: 329–337. 10.1086/511444

[44]

Gregersen N, Bross P, Vang S, Christensen JH. Protein misfolding and human disease. Annual Review of Genomics and Human Genetics. 2006; 7: 103–124. 10.1146/annurev.genom.7.080505.115737

[45]

Yadav K, Yadav A, Vashistha P, Pandey VP, Dwivedi UN. Protein Misfolding Diseases and Therapeutic Approaches. Current Protein & Peptide Science. 2019; 20: 1226–1245. 10.2174/1389203720666190610092840

[46]

Winklhofer KF, Tatzelt J, Haass C. The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases. The European Molecular Biology Organization. 2008; 27: 336–349. 10.1038/sj.emboj.7601930

[47]

Sweeney P, Park H, Baumann M, Dunlop J, Frydman J, Kopito R, et al. Protein misfolding in neurodegenerative diseases: implications and strategies. Translational Neurodegeneration. 2017; 6: 6. 10.1186/s40035-017-0077-5

[48]

Pathways of cellular proteostasis in aging and disease

Courtney L. Klaips, Gopal Gunanathan Jayaraj, F. Ulrich Hartl

The Journal of cell biology 10.1083/jcb.201709072

[49]

How many rare diseases are there?

Melissa Haendel, Nicole Vasilevsky, Deepak Unni et al.

Nature Reviews Drug Discovery 10.1038/d41573-019-00180-y

[50]

Turner TN, Douville C, Kim D, Stenson PD, Cooper DN, Chakravarti A, et al. Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns. Human Molecular Genetics. 2015; 24: 5995–6002. 10.1093/hmg/ddv309

Showing 50 of 176 references

Metrics

16

Citations

176

References

Details

Published: Dec 30, 2021
Vol/Issue: 26(12)
License: View

Authors

G

Gioena Pampalone