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The structure of a prophenoloxidase (PPO) from Anopheles gambiae provides new insights into the mechanism of PPO activation

Overview of attention for article published in BMC Biology, January 2016
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Title
The structure of a prophenoloxidase (PPO) from Anopheles gambiae provides new insights into the mechanism of PPO activation
Published in
BMC Biology, January 2016
DOI 10.1186/s12915-015-0225-2
Pubmed ID
Authors

Yingxia Hu, Yang Wang, Junpeng Deng, Haobo Jiang

Abstract

Phenoloxidase (PO)-catalyzed melanization is a universal defense mechanism of insects against pathogenic and parasitic infections. In mosquitos such as Anopheles gambiae, melanotic encapsulation is a resistance mechanism against certain parasites that cause malaria and filariasis. PO is initially synthesized by hemocytes and released into hemolymph as inactive prophenoloxidase (PPO), which is activated by a serine protease cascade upon recognition of foreign invaders. The mechanisms of PPO activation and PO catalysis have been elusive. Herein, we report the crystal structure of PPO8 from A. gambiae at 2.6 Å resolution. PPO8 forms a homodimer with each subunit displaying a classical type III di-copper active center. Our molecular docking and mutagenesis studies revealed a new substrate-binding site with Glu364 as the catalytic residue responsible for the deprotonation of mono- and di-phenolic substrates. Mutation of Glu364 severely impaired both the monophenol hydroxylase and diphenoloxidase activities of AgPPO8. Our data suggested that the newly identified substrate-binding pocket is the actual site for catalysis, and PPO activation could be achieved without withdrawing the conserved phenylalanine residue that was previously deemed as the substrate 'placeholder'. We present the structural and functional data from a mosquito PPO. Our results revealed a novel substrate-binding site with Glu364 identified as the key catalytic residue for PO enzymatic activities. Our data offered a new model for PPO activation at the molecular level, which differs from the canonical mechanism that demands withdrawing a blocking phenylalanine residue from the previously deemed substrate-binding site. This study provides new insights into the mechanisms of PPO activation and enzymatic catalysis of PO.

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Geographical breakdown

Country Count As %
United Kingdom 1 2%
Unknown 57 98%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 11 19%
Student > Master 9 16%
Researcher 8 14%
Student > Bachelor 7 12%
Professor > Associate Professor 5 9%
Other 10 17%
Unknown 8 14%
Readers by discipline Count As %
Agricultural and Biological Sciences 26 45%
Biochemistry, Genetics and Molecular Biology 10 17%
Environmental Science 4 7%
Chemistry 3 5%
Medicine and Dentistry 2 3%
Other 3 5%
Unknown 10 17%