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Protein Domain Evolution and Involvement in Diseases
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Protein Domain Evolution and Involvement in Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Informatics".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 18437

Special Issue Editors

Prof. Dr. Isabelle Callebaut

E-Mail Website
Guest Editor
IMPMC, CNRS-Sorbonne Université , Paris, France
Interests: structural bioinformatics; protein domain evolution; disorder; sequence analysis; molecular modelling
Dr. Tristan Bitard-Feildel

E-Mail Website
Guest Editor
Laboratoire de Biologie Computationnelle et Quantitative (LCQB), CNRS-Sorbonne Université, Paris, France
Interests: protein domain; protein evolution; protein sequence analysis; protein structure analysis; protein annotation; bioinformatics; methodological development; data analysis

Special Issue Information

Dear Colleagues,

Protein domains are structural and functional units harboring specific functions and orchestrating various processes, from enzyme catalysis to signal transduction. The use of protein domains in different contexts, a phenomenon called versatility or promiscuity, permits the molecular tinkering necessary for functional diversification and species evolution. Protein domains are evolutionarily conserved and several domain databases have been developed, providing statistical models allowing automatic protein annotation and experimental 3D structures enabling homology modeling and comparative analyses. These different levels of information (sequence, structure and evolution) available for protein domains can be used to understand the molecular mechanisms of human diseases, providing tools for diagnosis and specific therapeutic approaches. However, challenges remain, particularly for improving the sequence annotation of the dark proteome. This Special Issue will cover a selection of recent research topics in the field of protein domain discovery, annotation and evolution, with a relationship to human diseases. Research papers, up-to-date review articles, and commentaries are welcome.

Prof. Dr. Isabelle Callebaut
Dr. Tristan Bitard-Feildel
Guest Editors

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Keywords

  • protein domains/domain architectures
  • dark proteome
  • recent/novel protein domains
  • sequence analysis
  • comparative analysis
  • domain evolution
  • domain-based phylogeny
  • 3D structure modeling
  • prediction of mutation impacts
  • molecular dynamics simulations

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Published Papers (4 papers)

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Research

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17 pages, 3527 KiB  
Article
Early Postnatal Treatment with Valproate Induces Gad1 Promoter Remodeling in the Brain and Reduces Apnea Episodes in Mecp2-Null Mice
by Misa Ishiyama, Satoko Tamura, Hisanori Ito, Hiroki Takei, Manami Hoshi, Masatake Asano, Masayuki Itoh and Tetsuo Shirakawa
Int. J. Mol. Sci. 2019, 20(20), 5177; https://doi.org/10.3390/ijms20205177 - 18 Oct 2019
Cited by 4 | Viewed by 2927
Abstract
The deletion of Mecp2, the gene encoding methyl-CpG-binding protein 2, causes severe breathing defects and developmental anomalies in mammals. In Mecp2-null mice, impaired GABAergic neurotransmission is demonstrated at the early stage of life. GABAergic dysfunction in neurons in the rostral ventrolateral [...] Read more.
The deletion of Mecp2, the gene encoding methyl-CpG-binding protein 2, causes severe breathing defects and developmental anomalies in mammals. In Mecp2-null mice, impaired GABAergic neurotransmission is demonstrated at the early stage of life. GABAergic dysfunction in neurons in the rostral ventrolateral medulla (RVLM) is considered as a primary cause of breathing abnormality in Mecp2-null mice, but its molecular mechanism is unclear. Here, we report that mRNA expression levels of Gad1, which encodes glutamate decarboxylase 67 (GAD67), in the RVLM of Mecp2-null (Mecp2-/y, B6.129P2(C)-Mecp2tm1.1Bird/J) mice is closely related to the methylation status of its promoter, and valproate (VPA) can upregulate transcription from Gad1 through epigenetic mechanisms. The administration of VPA (300 mg/kg/day) together with L-carnitine (30 mg/kg/day) from day 8 to day 14 after birth increased Gad1 mRNA expression in the RVLM and reduced apnea counts in Mecp2-/y mice on postnatal day 15. Cytosine methylation levels in the Gad1 promoter were higher in the RVLM of Mecp2-/y mice compared to wild-type mice born to C57BL/6J females, while VPA treatment decreased the methylation levels in Mecp2-/y mice. Chromatin immunoprecipitation assay revealed that the VPA treatment reduced the binding of methyl-CpG binding domain protein 1 (MBD1) to the Gad1 promoter in Mecp2-/y mice. These results suggest that VPA improves breathing of Mecp2-/y mice by reducing the Gad1 promoter methylation, which potentially leads to the enhancement of GABAergic neurotransmission in the RVLM. Full article
(This article belongs to the Special Issue Protein Domain Evolution and Involvement in Diseases)
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9 pages, 1160 KiB  
Article
Investigating the Molecular Basis of the Aggregation Propensity of the Pathological D76N Mutant of Beta-2 Microglobulin: Role of the Denatured State
by Lorenzo Visconti, Francesca Malagrinò, Luca Broggini, Chiara Maria Giulia De Luca, Fabio Moda, Stefano Gianni, Stefano Ricagno and Angelo Toto
Int. J. Mol. Sci. 2019, 20(2), 396; https://doi.org/10.3390/ijms20020396 - 18 Jan 2019
Cited by 5 | Viewed by 3522
Abstract
Beta-2 microglobulin (β2m) is a protein responsible for a pathologic condition, known as dialysis-related amyloidosis (DRA), caused by its aggregation and subsequent amyloid formation. A naturally occurring mutation of β2m, D76N, presents a higher amyloidogenic propensity compared to the wild type counterpart. Since [...] Read more.
Beta-2 microglobulin (β2m) is a protein responsible for a pathologic condition, known as dialysis-related amyloidosis (DRA), caused by its aggregation and subsequent amyloid formation. A naturally occurring mutation of β2m, D76N, presents a higher amyloidogenic propensity compared to the wild type counterpart. Since the three-dimensional structure of the protein is essentially unaffected by the mutation, the increased aggregation propensity of D76N has been generally ascribed to its lower thermodynamic stability and increased dynamics. In this study we compare the equilibrium unfolding and the aggregation propensity of wild type β2m and D76N variant at different experimental conditions. Our data revealed a surprising effect of the D76N mutation in the residual structure of the denatured state, which appears less compact than that of the wild type protein. A careful investigation of the structural malleability of the denatured state of wild type β2m and D76N pinpoint a clear role of the denatured state in triggering the amyloidogenic propensity of the protein. The experimental results are discussed in the light of the previous work on β2m and its role in disease. Full article
(This article belongs to the Special Issue Protein Domain Evolution and Involvement in Diseases)
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Review

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14 pages, 589 KiB  
Review
Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review
by Livia Bernardi and Amalia C. Bruni
Int. J. Mol. Sci. 2019, 20(14), 3606; https://doi.org/10.3390/ijms20143606 - 23 Jul 2019
Cited by 20 | Viewed by 6598
Abstract
Inherited mutations in the Prion protein (PrP), encoded by the PRNP gene, have been associated with autosomal dominant neurodegenerative disorders, such as Creutzfeldt–Jacob disease (CJD), Gerstmann–Sträussler–Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI). Notably, PRNP mutations have also been described in clinical pictures [...] Read more.
Inherited mutations in the Prion protein (PrP), encoded by the PRNP gene, have been associated with autosomal dominant neurodegenerative disorders, such as Creutzfeldt–Jacob disease (CJD), Gerstmann–Sträussler–Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI). Notably, PRNP mutations have also been described in clinical pictures resembling other neurodegenerative diseases, such as frontotemporal dementia. Regarding the pathogenesis, it has been observed that these point mutations are located in the C-terminal region of the PRNP gene and, currently, the potential significance of the N-terminal domain has largely been underestimated. The purpose of this report is to review and provide current insights into the pathogenic mechanisms of PRNP mutations, emphasizing the differences between the C- and N-terminal regions and focusing, in particular, on the lesser-known flexible N-terminal, for which recent biophysical evidence has revealed a physical interaction with the globular C-terminal domain of the cellular prion protein (PrPC). Full article
(This article belongs to the Special Issue Protein Domain Evolution and Involvement in Diseases)
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20 pages, 6691 KiB  
Review
Evolution and Medical Significance of LU Domain−Containing Proteins
by Julie Maja Leth, Katrine Zinck Leth-Espensen, Kristian Kølby Kristensen, Anni Kumari, Anne-Marie Lund Winther, Stephen G. Young and Michael Ploug
Int. J. Mol. Sci. 2019, 20(11), 2760; https://doi.org/10.3390/ijms20112760 - 5 Jun 2019
Cited by 30 | Viewed by 4772
Abstract
Proteins containing Ly6/uPAR (LU) domains exhibit very diverse biological functions and have broad taxonomic distributions in eukaryotes. In general, they adopt a characteristic three-fingered folding topology with three long loops projecting from a disulfide-rich globular core. The majority of the members of this [...] Read more.
Proteins containing Ly6/uPAR (LU) domains exhibit very diverse biological functions and have broad taxonomic distributions in eukaryotes. In general, they adopt a characteristic three-fingered folding topology with three long loops projecting from a disulfide-rich globular core. The majority of the members of this protein domain family contain only a single LU domain, which can be secreted, glycolipid anchored, or constitute the extracellular ligand binding domain of type-I membrane proteins. Nonetheless, a few proteins contain multiple LU domains, for example, the urokinase receptor uPAR, C4.4A, and Haldisin. In the current review, we will discuss evolutionary aspects of this protein domain family with special emphasis on variations in their consensus disulfide bond patterns. Furthermore, we will present selected cases where missense mutations in LU domain−containing proteins leads to dysfunctional proteins that are causally linked to genesis of human disease. Full article
(This article belongs to the Special Issue Protein Domain Evolution and Involvement in Diseases)
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