scholarly journals Molecular Basis for N-terminal Alpha-Synuclein Acetylation by Human NatB

2020 ◽  
Author(s):  
Sunbin Deng ◽  
Buyan Pan ◽  
Leah Gottlieb ◽  
E. James Petersson ◽  
Ronen Marmorstein
Keyword(s):  
Hepatocellular Carcinoma ◽  
Candida Albicans ◽  
Small Molecule ◽  
Therapeutic Target ◽  
Molecular Basis ◽  
Alpha Synuclein ◽  
Substrate Selection ◽  
Disease Pathogenesis ◽  
Potential Therapeutic Target ◽  
Eukaryotic Proteins

AbstractNatB is one of three major N-terminal acetyltransferase (NAT) complexes (NatA-NatC), which co-translationally acetylate the N-termini of eukaryotic proteins. Its substrates account for about 21% of the human proteome, including well known proteins such as actin, tropomyosin, CDK2, and α-synuclein (αSyn). Human NatB (hNatB) mediated N-terminal acetylation of αSyn has been demonstrated to play key roles in Parkinson’s disease pathogenesis and as a potential therapeutic target for hepatocellular carcinoma. Here we report the cryo-EM structure of hNatB bound to a CoA-αSyn conjugate, together with structure-guided analysis of mutational effects on catalysis. This analysis reveals functionally important differences with human NatA and Candida albicans NatB, resolves key hNatB protein determinants for αSyn N-terminal acetylation, and identifies important residues for substrate-specific recognition and acetylation by NatB enzymes. These studies have implications for developing small molecule NatB probes and for understanding the mode of substrate selection by NAT enzymes.

scholarly journals Molecular basis for N-terminal alpha-synuclein acetylation by human NatB

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Sunbin Deng ◽  
Buyan Pan ◽  
Leah Gottlieb ◽  
E James Petersson ◽  
Ronen Marmorstein
Keyword(s):  
Hepatocellular Carcinoma ◽  
Candida Albicans ◽  
Small Molecule ◽  
Therapeutic Target ◽  
Molecular Basis ◽  
Alpha Synuclein ◽  
Human Proteome ◽  
Substrate Selection ◽  
Potential Therapeutic Target ◽  
Eukaryotic Proteins

NatB is one of three major N-terminal acetyltransferase (NAT) complexes (NatA-NatC), which co-translationally acetylate the N-termini of eukaryotic proteins. Its substrates account for about 21% of the human proteome, including well known proteins such as actin, tropomyosin, CDK2, and α-synuclein (αSyn). Human NatB (hNatB) mediated N-terminal acetylation of αSyn has been demonstrated to play key roles in the pathogenesis of Parkinson's disease and as a potential therapeutic target for hepatocellular carcinoma. Here we report the cryo-EM structure of hNatB bound to a CoA-αSyn conjugate, together with structure-guided analysis of mutational effects on catalysis. This analysis reveals functionally important differences with human NatA and Candida albicans NatB, resolves key hNatB protein determinants for αSyn N-terminal acetylation, and identifies important residues for substrate-specific recognition and acetylation by NatB enzymes. These studies have implications for developing small molecule NatB probes and for understanding the mode of substrate selection by NAT enzymes.

scholarly journals Regulation of TREM1-Mediated Inflammation in Hepatocellular Carcinoma Cells

Reports ◽  
2021 ◽  
Vol 4 (2) ◽  
pp. 17
Author(s):  
Vikrant Rai ◽  
Devendra K. Agrawal
Keyword(s):  
Hepatocellular Carcinoma ◽  
Vitamin D ◽  
Chronic Inflammation ◽  
Therapeutic Target ◽  
Primary Liver Cancer ◽  
Migration And Invasion ◽  
Potential Therapeutic Target ◽  
Mediators Of Inflammation ◽  
Tnf Α ◽  
Hcc Cells

Hepatocellular carcinoma (HCC), accounting for more than 90% of cases of primary liver cancer, is the third most common cause of cancer-related death worldwide. Chronic inflammation precedes the development of cirrhosis and HCC. TREM (triggering receptor expressed on myeloid cell)-1 is an inflammatory marker and amplifier of inflammation that signals through PI3K and ERK1/2 to activate transcription factors, resulting in increased secretion of pro-inflammatory cytokines, causing chronic inflammation and predisposing the liver to carcinogenesis. Thus, targeting TREM-1 in HCC might be a potential therapeutic target. A low level of vitamin D has been associated with chronic inflammation and poor prognosis in HCC. Thus, we evaluated the effect of vitamin D on TREM-1 expression in the HCC cell line. Additionally, the effects of high mobility group box-1, lipopolysaccharide, and transcription factor PU.1 on the expression of TREM-1 in normal liver cells and HCC cells have been investigated in the presence and absence of vitamin D. The results showed increased expression of TREM-1 in HCC cells and with IL-6, TNF-α, LPS, and rHMGB-1 and decreased expression with calcitriol. Calcitriol also attenuated the effect of IL-6, TNF-α, LPS, and rHMGB-1 on TREM-1. Calcitriol treatment attenuated the proliferation, migration, and invasion of HCC cells. These results (in vitro) provide molecular and biochemical evidence that calcitriol significantly attenuates the expression of mediators of inflammation, and thus might be used therapeutically together with conventional treatment to delay the progression of HCC. Additionally, the negative regulation of TREM-1 by PU.1 suggests PU.1 as a potential therapeutic target.

scholarly journals Integrative bioinformatics analysis identifies ROBO1 as a potential therapeutic target modified by miR-218 in hepatocellular carcinoma

Oncotarget ◽  
2017 ◽  
Vol 8 (37) ◽  
pp. 61327-61337 ◽  
Author(s):  
Junqing Wang ◽  
Yunyun Zhou ◽  
Xiaochun Fei ◽  
Xunhua Chen ◽  
Rui Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Therapeutic Target ◽  
Bioinformatics Analysis ◽  
Potential Therapeutic Target

scholarly journals TACC3 promotes stemness and is a potential therapeutic target in hepatocellular carcinoma

Oncotarget ◽  
2015 ◽  
Vol 6 (27) ◽  
pp. 24163-24177 ◽  
Author(s):  
Dong-Sheng Zhou ◽  
Hong-Bo Wang ◽  
Zhong-Guo Zhou ◽  
Yao-Jun Zhang ◽  
Qian Zhong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Therapeutic Target ◽  
Potential Therapeutic Target

scholarly journals Data on Adiponectin from 2010 to 2020: Therapeutic Target and Prognostic Factor for Liver Diseases?

2020 ◽  
Vol 21 (15) ◽  
pp. 5242 ◽  
Author(s):  
Misaq Heydari ◽  
María Eugenia Cornide-Petronio ◽  
Mónica B. Jiménez-Castro ◽  
Carmen Peralta
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Liver Disease ◽  
Therapeutic Target ◽  
Liver Diseases ◽  
Therapeutic Strategies ◽  
Potential Therapeutic Target ◽  
Surgical Interventions ◽  
Scientific Controversies

The review describes the role of adiponectin in liver diseases in the presence and absence of surgery reported in the literature in the last ten years. The most updated therapeutic strategies based on the regulation of adiponectin including pharmacological and surgical interventions and adiponectin knockout rodents, as well as some of the scientific controversies in this field, are described. Whether adiponectin could be a potential therapeutic target for the treatment of liver diseases and patients submitted to hepatic resection or liver transplantation are discussed. Furthermore, preclinical and clinical data on the mechanism of action of adiponectin in different liver diseases (nonalcoholic fatty disease, alcoholic liver disease, nonalcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma) in the absence or presence of surgery are evaluated in order to establish potential targets that might be useful for the treatment of liver disease as well as in the practice of liver surgery associated with the hepatic resections of tumors and liver transplantation.

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