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Protein Phosphorylation in Genetic Diseases
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Protein Phosphorylation in Genetic Diseases

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

Deadline for manuscript submissions: 15 April 2025 | Viewed by 3911

Special Issue Editors

Dr. Christian Borgo

E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, 35131 Padova, Italy
Interests: chronic myeloid leukemia; cystic fibrosis; glucose metabolism; drug-resistance; phosphorylation; protein kinase inhibitors; protein kinase ck2; CFTR
Special Issues, Collections and Topics in MDPI journals
Dr. Mauro Salvi

E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Padova, Padova, Italy
Interests: protein phosphorylation; acidic protein kinases; tyrosine kinases; kinase inhibitors, signal transduction; post-translational modifications; cancer; cystic fibrosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Protein phosphorylation is the most recurrent post-translational modification by which the properties of eukaryotic proteins can be reversibly changed. In a protein, the phosphorylation extent of tyrosine, serine, and threonine sites are regulated by the balance of the action of protein kinases and protein phosphatases. In humans, over 500 protein kinases generate a huge phosphoproteome including more than 200,000 individual phosphosites, and approximately 200 phosphatases are involved in their dephosphorylation. It is well known that an aberrant phosphorylation could take part to the pathogenesis of several human diseases, such as cancer, neurodegenerative diseases, diabetes. Likewise, inherited mutations in genes of specific protein kinases or phosphatases have been identified as the cause of different genetic diseases, such as Pfeiffer syndrome, Crouzon syndrome, Raine syndrome, Donohue syndrome, Noonan syndrome etc. Moreover, also pathological proteins involved in genetic disorders have been shown to have an aberrant function due to the alteration of their phosphorylation state, caused by the disease-associated mutation, including α-synuclein, tau, APP. In this perspective, over the years there has been a progressive interest in the development of drugs that target specific protein kinases and or phosphatases for the treatment of various genetic disorders. This Special Issue will cover the recent progress in all of the areas related to the involvement of protein phosphorylation in genetic diseases. Both original research articles and reviews are welcome.

Dr. Christian Borgo
Dr. Mauro Salvi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (2 papers)

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Research

31 pages, 3751 KiB  
Article
Potential Role of Protein Kinase FAM20C on the Brain in Raine Syndrome, an In Silico Analysis
by Icela Palma-Lara, Patricia García Alonso-Themann, Javier Pérez-Durán, Ricardo Godínez-Aguilar, José Bonilla-Delgado, Damián Gómez-Archila, Ana María Espinosa-García, Manuel Nolasco-Quiroga, Georgina Victoria-Acosta, Adolfo López-Ornelas, Juan Carlos Serrano-Bello, María Guadalupe Olguín-García and Carmen Palacios-Reyes
Int. J. Mol. Sci. 2023, 24(10), 8904; https://doi.org/10.3390/ijms24108904 - 17 May 2023
Cited by 1 | Viewed by 1611
Abstract
FAM20C (family with sequence similarity 20, member C) is a serine/threonine-specific protein kinase that is ubiquitously expressed and mainly associated with biomineralization and phosphatemia regulation. It is mostly known due to pathogenic variants causing its deficiency, which results in Raine syndrome (RNS), a [...] Read more.
FAM20C (family with sequence similarity 20, member C) is a serine/threonine-specific protein kinase that is ubiquitously expressed and mainly associated with biomineralization and phosphatemia regulation. It is mostly known due to pathogenic variants causing its deficiency, which results in Raine syndrome (RNS), a sclerosing bone dysplasia with hypophosphatemia. The phenotype is recognized by the skeletal features, which are related to hypophosphorylation of different FAM20C bone-target proteins. However, FAM20C has many targets, including brain proteins and the cerebrospinal fluid phosphoproteome. Individuals with RNS can have developmental delay, intellectual disability, seizures, and structural brain defects, but little is known about FAM20C brain-target-protein dysregulation or about a potential pathogenesis associated with neurologic features. In order to identify the potential FAM20C actions on the brain, an in silico analysis was conducted. Structural and functional defects reported in RNS were described; FAM20C targets and interactors were identified, including their brain expression. Gene ontology of molecular processes, function, and components was completed for these targets, as well as for potential involved signaling pathways and diseases. The BioGRID and Human Protein Atlas databases, the Gorilla tool, and the PANTHER and DisGeNET databases were used. Results show that genes with high expression in the brain are involved in cholesterol and lipoprotein processes, plus axo-dendritic transport and the neuron part. These results could highlight some proteins involved in the neurologic pathogenesis of RNS. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Genetic Diseases)
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17 pages, 4549 KiB  
Article
The Oligomerization Domains of the APC Protein Mediate Liquid-Liquid Phase Separation That Is Phosphorylation Controlled
by Shachar G. Bressler, Amit Mitrany, Alon Wenger, Inke Näthke and Assaf Friedler
Int. J. Mol. Sci. 2023, 24(7), 6478; https://doi.org/10.3390/ijms24076478 - 30 Mar 2023
Cited by 3 | Viewed by 1629
Abstract
One of the most important properties of intrinsically disordered proteins is their ability to undergo liquid-liquid phase separation and form droplets. The Adenomatous Polyposis Coli (APC) protein is an IDP that plays a key role in Wnt signaling and mutations in Apc initiate [...] Read more.
One of the most important properties of intrinsically disordered proteins is their ability to undergo liquid-liquid phase separation and form droplets. The Adenomatous Polyposis Coli (APC) protein is an IDP that plays a key role in Wnt signaling and mutations in Apc initiate cancer. APC forms droplets via its 20R domains and self-association domain (ASAD) and in the context of Axin. However, the mechanism involved is unknown. Here, we used peptides to study the molecular mechanism and regulation of APC droplet formation. We found that a peptide derived from the ASAD of APC-formed droplets. Peptide array screening showed that the ASAD bound other APC peptides corresponding to the 20R3 and 20R5 domains. We discovered that the 20R3/5 peptides also formed droplets by themselves and mapped specific residues within 20R3/5 that are necessary for droplet formation. When incubated together, the ASAD and 20R3/5 did not form droplets. Thus, the interaction of the ASAD with 20R3 and 20R5 may regulate the droplet formation as a means of regulating different cellular functions. Phosphorylation of 20R3 or 20R5 at specific residues prevented droplet formation of 20R3/5. Our results reveal that phosphorylation and the ability to undergo liquid-liquid phase separation, which are both important properties of intrinsically disordered proteins, are related to each other in APC. Phosphorylation inhibited the liquid-liquid phase separation of APC, acting as an ‘on-off’ switch for droplet formation. Phosphorylation may thus be a common mechanism regulating LLPS in intrinsically disordered proteins. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Genetic Diseases)
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