scholarly journals Protein kinase C gamma mutations in spinocerebellar ataxia 14 increase kinase activity and alter membrane targeting

Brain ◽  
2004 ◽  
Vol 128 (2) ◽  
pp. 436-442 ◽  
Author(s):  
D. S. Verbeek
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Spinocerebellar Ataxia ◽  
Kinase Activity ◽  
Membrane Targeting ◽  
Kinase C ◽  
Protein Kinase C Gamma

scholarly journals Protein Kinase C gamma Mutations Drive Spinocerebellar Ataxia Type 14 by Impairing Autoinhibition

2021 ◽  
Author(s):  
Caila A. Pilo ◽  
Alexandr P. Kornev ◽  
Timothy R. Baffi ◽  
Maya T. Kunkel ◽  
Liang-Chin Huang ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Spinocerebellar Ataxia ◽  
Spinocerebellar Ataxia Type ◽  
Cell Degeneration ◽  
Basal Activity ◽  
Kinase C ◽  
Protein Kinase C Gamma ◽  
Spinocerebellar Ataxia Type 14 ◽  
C1 Domains

Spinocerebellar ataxia type 14 (SCA14) is a neurodegenerative disease caused by germline mutations in the diacylglycerol (DG)/Ca2+-regulated protein kinase C gamma (PKCγ), leading to Purkinje cell degeneration and progressive cerebellar dysfunction. The majority of the approximately 50 mutations identified in PKCγ cluster to the DG-sensing C1 domains. Here, we use a FRET-based activity reporter to show that ataxia-associated PKCγ mutations enhance basal activity by compromising autoinhibition. Although impaired autoinhibition generally leads to PKC degradation, the C1 domain mutations protect PKCγ from phorbol ester-induced downregulation. Furthermore, it is the degree of disrupted autoinhibition, not changes in the amplitude of agonist-stimulated activity, that correlate with disease severity. Specifically, a SCA14 mutation in which phenylalanine 48 in the C1A domain is deleted had high basal activity both in cells and in vitro, yet was unresponsive to agonist stimulation. Validating that the pathology arises from disrupted autoinhibition, we show that the degree of impaired autoinhibition correlates inversely with age of disease onset in patients: mutations that cause high basal activity are associated with early onset, whereas those that only modestly increase basal activity, including a previously undescribed mutation D115Y, are associated with later onset. Molecular modeling indicates that almost all SCA14 mutations that are not in the C1 domains are at interfaces with the C1B domain, and bioinformatics analysis reveals that mutations in the C1B domain are under-represented in cancer. Thus, clustering of SCA14 mutations to the C1B domain provides a unique mechanism to enhance PKCγ basal activity while protecting the enzyme from downregulation.

A novel mutation in the C2 domain of protein kinase C gamma associated with spinocerebellar ataxia type 14

2013 ◽  
Vol 260 (6) ◽  
pp. 1664-1666 ◽  
Author(s):  
Takehiro Ueda ◽  
Tsuneyoshi Seki ◽  
Kimitaka Katanazaka ◽  
Kenji Sekiguchi ◽  
Kazuhiro Kobayashi ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Spinocerebellar Ataxia ◽  
Novel Mutation ◽  
Spinocerebellar Ataxia Type ◽  
C2 Domain ◽  
Kinase C ◽  
Protein Kinase C Gamma ◽  
Spinocerebellar Ataxia Type 14

Increased protein kinase C gamma activity induces Purkinje cell pathology in a mouse model of spinocerebellar ataxia 14

2014 ◽  
Vol 70 ◽  
pp. 1-11 ◽  
Author(s):  
Jingmin Ji ◽  
Melanie L. Hassler ◽  
Etsuko Shimobayashi ◽  
Nagendher Paka ◽  
Raphael Streit ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Mouse Model ◽  
Purkinje Cell ◽  
Spinocerebellar Ataxia ◽  
Gamma Activity ◽  
Kinase C ◽  
Protein Kinase C Gamma

scholarly journals Identification of Key Phospholipids That Bind and Activate Atypical PKCs

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 45
Author(s):  
Suresh Velnati ◽  
Sara Centonze ◽  
Federico Girivetto ◽  
Daniela Capello ◽  
Ricardo M. Biondi ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phosphatidic Acid ◽  
Kinase Activity ◽  
Membrane Lipids ◽  
Atypical Protein Kinase C ◽  
Atypical Protein Kinase ◽  
Kinase C ◽  
Specific Regulation ◽  
Phosphatidylinositol 4

PKCζ and PKCι/λ form the atypical protein kinase C subgroup, characterised by a lack of regulation by calcium and the neutral lipid diacylglycerol. To better understand the regulation of these kinases, we systematically explored their interactions with various purified phospholipids using the lipid overlay assays, followed by kinase activity assays to evaluate the lipid effects on their enzymatic activity. We observed that both PKCζ and PKCι interact with phosphatidic acid and phosphatidylserine. Conversely, PKCι is unique in binding also to phosphatidylinositol-monophosphates (e.g., phosphatidylinositol 3-phosphate, 4-phosphate, and 5-phosphate). Moreover, we observed that phosphatidylinositol 4-phosphate specifically activates PKCι, while both isoforms are responsive to phosphatidic acid and phosphatidylserine. Overall, our results suggest that atypical Protein kinase C (PKC) localisation and activity are regulated by membrane lipids distinct from those involved in conventional PKCs and unveil a specific regulation of PKCι by phosphatidylinositol-monophosphates.

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