Identification and characterization of PKCγ, a kinase associated with SCA14, as an amyloidogenic protein
| Autor: | Takehiko Ueyama, Hirokazu Hirai, Anton N. Shuvaev, Norio Sakai, Kazuhiro Irie, Takuya Sugimoto, Naoko Adachi, Michele Vendruscolo, Sally Danno, Toshihiko Shirafuji, Daizo Hamada, Naoaki Saito, Takahiro Seki, Hideyuki Takahashi |
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| Rok vydání: | 2014 |
| Předmět: |
Amyloid
Kinase General Medicine Biology medicine.disease Fibril Protein Structure Tertiary Serine Biochemistry Mutation Genetics Spinocerebellar ataxia medicine Humans Spinocerebellar Ataxias Threonine Molecular Biology Genetics (clinical) Protein kinase C Protein Kinase C C1 domain Protein Binding Spinocerebellar Degenerations |
| Zdroj: | Human molecular genetics. 24(2) |
| ISSN: | 1460-2083 |
| Popis: | Amyloid assemblies are associated with a wide range of human disorders, including Alzheimer's and Parkinson's diseases. Here, we identify protein kinase C (PKC) γ, a serine/threonine kinase mutated in the neurodegenerative disease spinocerebellar ataxia type 14 (SCA14), as a novel amyloidogenic protein with no previously characterized amyloid-prone domains. We found that overexpression of PKCγ in cultured cells, as well as in vitro incubation of PKCγ without heat or chemical denaturants, causes amyloid-like fibril formation of this protein. We also observed that SCA14-associated mutations in PKCγ accelerate the amyloid-like fibril formation both in cultured cells and in vitro. We show that the C1A and kinase domains of PKCγ are involved in its soluble dimer and aggregate formation and that SCA14-associated mutations in the C1 domain cause its misfolding and aggregation. Furthermore, long-term time-lapse imaging indicates that aggregates of mutant PKCγ are highly toxic to neuronal cells. Based on these findings, we propose that PKCγ could form amyloid-like fibrils in physiological and/or pathophysiological conditions such as SCA14. More generally, our results provide novel insights into the mechanism of amyloid-like fibril formation by multi-domain proteins. |
| Databáze: | OpenAIRE |
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