Modulation of Lipid Kinase PI4KIIα Activity and Lipid Raft Association of Presenilin 1 Underlies γ-Secretase Inhibition by Ginsenoside (20S)-Rg3

Kang, Min Suk; Baek, Seung‐Hoon; Chun, Yoon S.; Moore, Ann Zenobia; Landman, Natalie; Berman, Diego E.; Yang, Hyun Ok; Morishima-Kawashima, Maho; Osawa, Satoko; Funamoto, Satoru; Ihara, Yasuo; Park, Jeong Hill; Chung, Sungkwon; Kim, Tae‐Wan

doi:10.1074/jbc.m112.445734

Cited by 37 publications

(44 citation statements)

References 85 publications

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“…PI4KIIα has a specific cysteine-rich motif (-CCPCC-); its kinase activity critically depends on palmitoylation of the cysteine-rich motif152829 and is modulated by cholesterol, amyloid-β peptide, mastoparan, 25-hydroxycholesterol and ginsenoside (20S)Rg3 via changing the membrane environment as suggested previously14303132.…”

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confidence: 85%

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Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα

Zhou

et al. 2014

Nat Commun

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Phosphatidylinositol 4-kinase IIα (PI4KIIα), a membrane-associated PI kinase, plays a central role in cell signalling and trafficking. Its kinase activity critically depends on palmitoylation of its cysteine-rich motif (-CCPCC-) and is modulated by the membrane environment. Lack of atomic structure impairs our understanding of the mechanism regulating kinase activity. Here we present the crystal structure of human PI4KIIα in ADP-bound form. The structure identifies the nucleotide-binding pocket that differs notably from that found in PI3Ks. Two structural insertions, a palmitoylation insertion and an RK-rich insertion, endow PI4KIIα with the ‘integral’ membrane-binding feature. Molecular dynamics simulations, biochemical and mutagenesis studies reveal that the palmitoylation insertion, containing an amphipathic helix, contributes to the PI-binding pocket and anchors PI4KIIα to the membrane, suggesting that fluctuation of the palmitoylation insertion affects PI4KIIα’s activity. We conclude from our results that PI4KIIα’s activity is regulated indirectly through changes in the membrane environment.

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confidence: 85%

“…Its dysfunction contributes to tumour growth6, spastic paraplegia11, Gaucher’s disease12 and Alzheimer’s disease1314, suggesting PI4KIIα as a drug target.…”

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confidence: 99%

Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα

Zhou

et al. 2014

Nat Commun

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“…Of the 12 ginsenosides, CK, F 1 , Rh 1 , and Rh 2 were predicted to pass the BBB and ADMET analysis predicted toxic effects for ginsenosides Ro and ginsenoside Rg 1 , while Rf showed low oral absorption in human gastrointestinal tract. These results suggest that of the seven ginsenosides demonstrating BACE1 (Kang et al 2013) Rg 3 enhanced neprilysin (NEP, rate-limiting enzyme in A" degradation) gene expression. Caused a reduction in A"(1-40) and A"(1-42).…”

Section: Ginsengmentioning

confidence: 91%

Brain Food for Alzheimer-Free Ageing: Focus on Herbal Medicines

Hügel

2015

Advances in Experimental Medicine and Biology

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Healthy brain aging and the problems of dementia and Alzheimer's disease (AD) are a global concern. Beyond 60 years of age, most, if not everyone, will experience a decline in cognitive skills, memory capacity and changes in brain structure. Longevity eventually leads to an accumulation of amyloid plaques and/or tau tangles, including some vascular dementia damage. Therefore, lifestyle choices are paramount to leading either a brain-derived or a brain-deprived life. The focus of this review is to critically examine the evidence, impact, influence and mechanisms of natural products as chemopreventive agents which induce therapeutic outcomes that modulate the aggregation process of beta-amyloid (Aβ), providing measureable cognitive benefits in the aging process. Plants can be considered as chemical factories that manufacture huge numbers of diverse bioactive substances, many of which have the potential to provide substantial neuroprotective benefits. Medicinal herbs and health food supplements have been widely used in Asia since over 2,000 years. The phytochemicals utilized in traditional Chinese medicine have demonstrated safety profiles for human consumption. Many herbs with anti-amyloidogenic activity, including those containing polyphenolic constituents such as green tea, turmeric, Salvia miltiorrhiza, and Panax ginseng, are presented. Also covered in this review are extracts from kitchen spices including cinnamon, ginger, rosemary, sage, salvia herbs, Chinese celery and many others some of which are commonly used in herbal combinations and represent highly promising therapeutic natural compounds against AD. A number of clinical trials conducted on herbs to counter dementia and AD are discussed.

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“…Although in some cell types, PI(4)P production at the PM is performed by PI4KIII (Nakatsu et al, 2012), PI4KII has also been shown to control cellular levels of PI(4,5)P 2 (Pan et al, 2008;Chu et al, 2010;Kang et al, 2013). Indeed, despite the fact that in several cell types PI4KII localizes primarily to the transGolgi network and endosomes (Wang et al, 2003;Salazar et al, 2005;Balla and Balla, 2006;Minogue et al, 2006), a portion of PI4KII can be recruited to the PM (Wei et al, 2002;PizarroCerdá et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Rab27a controls HIV-1 assembly by regulating plasma membrane levels of phosphatidylinositol 4,5-bisphosphate

Gerber¹,

Cabrini²,

Jancic³

et al. 2015

J Exp Med

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Modulation of Lipid Kinase PI4KIIα Activity and Lipid Raft Association of Presenilin 1 Underlies γ-Secretase Inhibition by Ginsenoside (20S)-Rg3

Cited by 37 publications

References 85 publications

Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα

Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα

Brain Food for Alzheimer-Free Ageing: Focus on Herbal Medicines

Rab27a controls HIV-1 assembly by regulating plasma membrane levels of phosphatidylinositol 4,5-bisphosphate

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