Vasopressin-induced serine 269 phosphorylation reduces Sipa1l1 (signal-induced proliferation-associated 1 like 1)-mediated aquaporin-2 endocytosis.
The abundance of integral membrane proteins in the plasma membrane is determined by a dynamic balance between exocytosis and endocytosis, which can often be regulated by physiological stimuli. Here, we describe a mechanism that accounts for the ability of the peptide hormone vasopressin to regulate water excretion via a phosphorylation-dependent modulation of the PDZ domain-ligand interaction involving the water channel protein aquaporin-2. We discovered that the PDZ domain-containing protein Sipa1l1 (signal-induced proliferation-associated 1 like 1) binds to the cytoplasmic PDZ-ligand motif of aquaporin-2 and accelerates its endocytosis in the absence of vasopressin. Vasopressin-induced aquaporin-2 phosphorylation within the type I PDZ-ligand motif disrupted the interaction, in association with reduced aquaporin-2 endocytosis and prolonged plasma membrane aquaporin-2 retention. This phosphorylation-dependent alteration in the PDZ domain-ligand interaction was explained by 3D structural models, which showed a hormone-regulated mechanism that controls osmotic water transport and systemic water balance in mammals.
From the Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
Po-Jen
PJ
Wang
From the Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
Shu-Ting
ST
Lin
From the Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
Shao-Hsuan
SH
Liu
From the Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
Kuang-Ting
KT
Kuo
the Department of Agricultural Chemistry, National Taiwan University, Taipei 10617, Taiwan, and.
Chun-Hua
CH
Hsu
the Systems Biology Center, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1603.
Mark A
MA
Knepper
From the Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei 10051, Taiwan, mjyu@ntu.edu.tw.
Ming-Jiun
MJ
Yu
D000818:Animals; D051399:Aquaporin 2 / Q000737:chemistry* / Q000235:genetics; D004705:Endocytosis; D020690:GTPase-Activating Proteins / Q000737:chemistry* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D000072417:Protein Domains; D021381:Protein Transport; D040901:Proteomics; D034741:RNA, Small Interfering / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D014667:Vasopressins / Q000737:chemistry*; D014867:Water / Q000737:chemistry
C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D020690:GTPase-Activating Proteins; D008024:Ligands; D034741:RNA, Small Interfering; C543508:Sipa1l1 protein, mouse; D014867:Water; D014667:Vasopressins; D012694:Serine
AQP2; PDZ domain; Sipa1l1; aquaporin; kidney; phosphorylation; renal physiology; vasopressin