TAILIEUCHUNG - Báo cáo khoa học: Functional role of the linker region in purified human P-glycoprotein

Human P-glycoprotein (P-gp), which conveys multidrug resistance, is an ATP-dependent drug efflux pump that transports a wide variety of struc-turally unrelated compounds out of cells. P-gp possesses a ‘linker region’ of 75 amino acids that connects two homologous halves, each of which contain a transmembrane domain followed by a nucleotide-binding domain. | Functional role of the linker region in purified human P-glycoprotein Tomomi Sato1 Atsushi Kodan2 Yasuhisa Kimura3 Kazumitsu Ueda2 3 Toru Nakatsu1 and Hiroaki Kato1 1 Department of StructuralBiology Graduate Schoolof PharmaceuticalSciences Kyoto University Kyoto Japan 2 Institute for Integrated Cell-MaterialSciences Kyoto University Kyoto Japan 3 Division of Applied Life Sciences Graduate Schoolof Agriculture Kyoto University Kyoto Japan Keywords ATPase activity limited proteolysis linker region MDR1 P-glycoprotein Correspondence H. Kato Graduate School of Pharmaceutical Sciences Kyoto University 46-29 Yoshida-Shimo-Adachi-cho Sakyo-ku Kyoto 606-8501 Japan Fax 81 75 753 9272 Tel 81 75 753 4617 E-mail katohiro@ Received 28 December 2008 revised 19 April 2009 accepted 23 April 2009 doi Human P-glycoprotein P-gp which conveys multidrug resistance is an ATP-dependent drug efflux pump that transports a wide variety of structurally unrelated compounds out of cells. P-gp possesses a linker region of 75 amino acids that connects two homologous halves each of which contain a transmembrane domain followed by a nucleotide-binding domain. To investigate the role of the linker region purified human P-gp was cleaved by proteases at the linker region and then compared with native P-gp. Based on a verapamil-stimulated ATP hydrolase assay sizeexclusion chromatography analysis and a thermo-stability assay cleavage of the P-gp linker did not directly affect the preservation of the overall structure or the catalytic process in ATP hydrolysis. However linker cleavage increased the kcat values both with substrate ksub and without substrate kbasal but decreased the ksub kbasal values of all 10 tested substrates. The former result indicates that cleaving the linker activates P-gp while the latter result suggests that the linker region maintains the tightness of coupling between the ATP hydrolase reaction and substrate recognition. .

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• is an ATP dependent drug efflux pump that transports a wide variety of struc turally unrelated compounds out of cells
• P gp possesses a ‘linker region’ of75 amino acids that connects two homologous halves
• each of which contain a transmembrane domain followed by a nucleotide binding domain
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