期刊
CELLS
卷 10, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/cells10020404
关键词
PARK7; parkinson disease; neurodegenerative disease; protease; glycase; TAILS; proteomics; degradation; lysosome; cathepsin b
类别
资金
- DFG [CRC 850, PA 2807/3-1, SCHI 871/11-1, SCHI 871/15-1, GR 4553/5-1]
- canton of Grisons [628]
- Hans Groeber Foundation
DJ-1 is a crucial component of cellular proteomes, with its C-terminal helix 8 playing a key role in deglycation activity. The presence or absence of helix 8 in DJ-1 significantly impacts mitochondrial and lysosomal biology. The pleiotropic nature of DJ-1 is further demonstrated by its indirect modulation of lysosomal protease activity.
DJ-1 is an abundant and ubiquitous component of cellular proteomes. DJ-1 supposedly exerts a wide variety of molecular functions, ranging from enzymatic activities as a deglycase, protease, and esterase to chaperone functions. However, a consensus perspective on its molecular function in the cellular context has not yet been reached. Structurally, the C-terminal helix 8 of DJ-1 has been proposed to constitute a propeptide whose proteolytic removal transforms a DJ-1 zymogen to an active hydrolase with potential proteolytic activity. To better understand the cell-contextual functionality of DJ-1 and the role of helix 8, we employed post-mitotically differentiated, neuron-like SH-SY5Y neuroblastoma cells with stable over-expression of full length DJ-1 or DJ-1 lacking helix 8 (Delta H8), either with a native catalytically active site (C106) or an inactive site (C106A active site mutation). Global proteome comparison of cells over-expressing DJ-1 Delta H8 with native or mutated active site cysteine indicated a strong impact on mitochondrial biology. N-terminomic profiling however did not highlight direct protease substrate candidates for DJ-1 Delta H8, but linked DJ-1 to elevated levels of activated lysosomal proteases, albeit presumably in an indirect manner. Finally, we show that DJ-1 Delta H8 loses the deglycation activity of full length DJ-1. Our study further establishes DJ-1 as deglycation enzyme. Helix 8 is essential for the deglycation activity but dispensable for the impact on lysosomal and mitochondrial biology; further illustrating the pleiotropic nature of DJ-1.
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