Peptidylarginine deiminase modulates the physiological roles of enolase via citrullination: links between altered multifunction of enolase and neurodegenerative diseases
| Autor: | Byungki Jang, Eun-Kyoung Choi, Mira Park, Richard I. Carp, Yong-Sun Kim, Akihito Ishigami, Jin-Kyu Choi, Yong-Chul Jeon, Naoki Maruyama, Jae-Il Kim |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Hydrolases medicine.drug_class Blotting Western Lysine Enolase Monoclonal antibody Biochemistry Creutzfeldt-Jakob Syndrome Immunoenzyme Techniques Mice chemistry.chemical_compound Alzheimer Disease Biomarkers Tumor medicine Animals Humans Molecular Biology Aged Aged 80 and over Mice Inbred BALB C biology Tumor Suppressor Proteins Leupeptin Antibodies Monoclonal Brain Citrullination Plasminogen Cell Biology Molecular biology Peptide Fragments Recombinant Proteins Frontal Lobe DNA-Binding Proteins Blot Enolase 2 chemistry Case-Control Studies Phosphopyruvate Hydratase Aminocaproic Acid Protein-Arginine Deiminases biology.protein Citrulline Female Antibody Carrier Proteins Protein Processing Post-Translational |
| Zdroj: | Biochemical Journal. 445:183-192 |
| ISSN: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bj20120025 |
| Popis: | The citrullination of enolase by PAD (peptidylarginine deiminase) has emerged as an important post-translational modification in human disorders; however, the physiological function of citrullination remains unknown. In the present study, we report that citrullination diversely regulates the biological functions of ENO1 (α-enolase) and NSE (neuron-specific enolase). We developed three mouse IgG1 monoclonal antibodies with specificity to the following: (i) citrullination of Arg9 of ENO1 [ENO1Cit9; anti-CE1 (citrullinated enolase 1) antibody]; (ii) citrullination of Arg9 in ENO1 and NSE (ENO1Cit9/NSECit9; anti-CE1/2 antibody); and (iii) citrullination of Arg429 of NSE (NSECit429; anti-CE2 antibody). Regardless of the total protein expression level, the levels of ENO1Cit9 and NSECit429 were elevated, and their immunoreactivities were also increased in cortical neuronal cells or around blood vessels in the frontal cortex of patients with sporadic Creutzfeldt-Jakob disease and Alzheimer's disease compared with controls. In a time- and dose-dependent manner, PAD negatively regulated enolase activity via citrullination, and enolase in diseased patients was more inactive than in controls. Interestingly, the citrullination of enolase effectively promoted its proteolytic degradation by Ca2+-dependent calpain-1, and leupeptin (calpain inhibitor I) abrogated this degradation. Surprisingly, using an affinity assay, the citrullination of enolase enhanced its plasminogen-binding affinity, which was blocked by the lysine analogue ϵ-aminocaproic acid. These findings suggest that PAD-mediated citrullination regulates the diverse physiological activities of enolase and that CE may be a candidate diagnostic/prognostic factor for degenerative diseases. |
| Databáze: | OpenAIRE |
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