title: Structural insight into the activation mechanism of human pancreatic prophospholipase A2.
abstract: Pancreatic phospholipase A2 (phospholipase A2 group 1B, G1B) belongs to the superfamily of secreted phospholipase A2 (PLA2) enzymes. G1B has been proposed to be a potential target for diseases such as hypertension, obesity, and diabetes. Human pancreatic prophospholipase A2 (pro-hG1B) is activated by cleavage of the first seven-residue propeptide (phospholipase A2 propeptide, PROP). However, questions still remain on the mode of action for pro-hG1B. In this work, we expressed pro-hG1B in Pichia pastoris and determined the crystal structure at 1.55-A resolution. The x-ray structure demonstrates that pro-hG1B forms a trimer. In addition, PROP occupies the catalytic cavity and can be self-cleaved at 37 degrees C. A new membrane-bound surface and activation mechanism are proposed based on the trimeric model of pro-hG1B. We also propose a new autoproteolytic mechanism for pro-hG1B by the reaction triad Asp49-Arg0-Ser(-2) that is similar to the serine protease catalytic triad.
authors.affiliation: From the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China; Graduate University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: From the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Yi
authors.affiliation: From the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Feng
authors.affiliation: From the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China; School of Life Sciences, University of Science and Technology of China, Hefei 230027, China. Electronic address: chen_ling@gibh.ac.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: From the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China; School of Life Sciences, University of Science and Technology of China, Hefei 230027, China. Electronic address: liu_jinsong@gibh.ac.cn.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D002384:Catalysis; D003461:Crystallography; D004789:Enzyme Activation / Q000502:physiology; D054500:Group IB Phospholipases A2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010843:Pichia / Q000235:genetics; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D054500:Group IB Phospholipases A2; C516202:PLA2G1B protein, human