Crystal structure of human aquaporin 4 at 1.8 Å and its mechanism of conductance

Aquaporin (AQP) 4 is the predominant water channel in the mammalian brain, abundantly expressed in the blood–brain and brain–cerebrospinal fluid interfaces of glial cells. Its function in cerebral water balance has implications in neuropathological disorders, including brain edema, stroke, and head injuries. The 1.8-Å crystal structure reveals the molecular basis for the water selectivity of the channel. Unlike the case in the structures of water-selective AQPs AqpZ and AQP1, the asparagines of the 2 Asn-Pro-Ala motifs do not hydrogen bond to the same water molecule; instead, they bond to 2 different water molecules in the center of the channel. Molecular dynamics simulations were performed to ask how this observation bears on the proposed mechanisms for how AQPs remain totally insulating to any proton conductance while maintaining a single file of hydrogen bonded water molecules throughout the channel.

[1]  Richard Neutze,et al.  Aquaporin gating. , 2006, Current opinion in structural biology.

[2]  Bong-Gyoon Han,et al.  Structural basis of water-specific transport through the AQP1 water channel , 2001, Nature.

[3]  Collaborative Computational,et al.  The CCP4 suite: programs for protein crystallography. , 1994, Acta crystallographica. Section D, Biological crystallography.

[4]  J. Badaut,et al.  Aquaporins in the brain: from aqueduct to “multi-duct” , 2007, Metabolic Brain Disease.

[5]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[6]  Kazushi Kimura,et al.  Implications of the aquaporin-4 structure on array formation and cell adhesion. , 2006, Journal of molecular biology.

[7]  L. Miercke,et al.  Crystal structure of the aquaglyceroporin PfAQP from the malarial parasite Plasmodium falciparum , 2008, Nature Structural &Molecular Biology.

[8]  Arieh Warshel,et al.  The barrier for proton transport in aquaporins as a challenge for electrostatic models: The role of protein relaxation in mutational calculations , 2006, Proteins.

[9]  H. Brismar,et al.  Water permeability of aquaporin-4 is decreased by protein kinase C and dopamine. , 2002, American journal of physiology. Renal physiology.

[10]  A. Warshel,et al.  What really prevents proton transport through aquaporin? Charge self-energy versus proton wire proposals. , 2003, Biophysical journal.

[11]  O. P. Ottersen,et al.  Anchoring of aquaporin-4 in brain: Molecular mechanisms and implications for the physiology and pathophysiology of water transport , 2004, Neuroscience.

[12]  Yi Wang,et al.  Structural mechanism of plant aquaporin gating , 2006, Nature.

[13]  D. Kerr,et al.  Neuromyelitis optica pathogenesis and aquaporin 4 , 2008 .

[14]  Peter Agre,et al.  Structural basis for conductance by the archaeal aquaporin AqpM at 1.68 A. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[15]  L. Barnett,et al.  Differential growth patterns in SCID mice of patient-derived chronic myelogenous leukemias , 1998, Bone Marrow Transplantation.

[16]  Robert M Stroud,et al.  Architecture and Selectivity in Aquaporins: 2.5 Å X-Ray Structure of Aquaporin Z , 2003, PLoS biology.

[17]  T. Nakada,et al.  Inhibition of aquaporin 4 by antiepileptic drugs. , 2009, Bioorganic & medicinal chemistry.

[18]  K. Schulten,et al.  Control of the Selectivity of the Aquaporin Water Channel Family by Global Orientational Tuning , 2002, Science.

[19]  J. Frøkiaer,et al.  A current view of the mammalian aquaglyceroporins. , 2008, Annual review of physiology.

[20]  B. L. de Groot,et al.  Quaternary Ammonium Compounds as Water Channel Blockers , 2006, Journal of Biological Chemistry.

[21]  Pierre J Magistretti,et al.  Aquaporins in Brain: Distribution, Physiology, and Pathophysiology , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[22]  D. Fu,et al.  Structure of a glycerol-conducting channel and the basis for its selectivity. , 2000, Science.

[23]  A. Verkman,et al.  Molecular cloning of a mercurial-insensitive water channel expressed in selected water-transporting tissues. , 1994, The Journal of biological chemistry.

[24]  C.J.T. de Grotthuss.  Memoir on the decomposition of water and of the bodies that it holds in solution by means of galvanic electricity , 2006 .

[25]  Klaus Schulten,et al.  Charge delocalization in proton channels, I: the aquaporin channels and proton blockage. , 2007, Biophysical journal.

[26]  A. Verkman,et al.  Evidence against involvement of aquaporin-4 in cell-cell adhesion. , 2008, Journal of molecular biology.

[27]  Jay Painter,et al.  Electronic Reprint Biological Crystallography Optimal Description of a Protein Structure in Terms of Multiple Groups Undergoing Tls Motion Biological Crystallography Optimal Description of a Protein Structure in Terms of Multiple Groups Undergoing Tls Motion , 2005 .

[28]  K. Schulten,et al.  The mechanism of proton exclusion in aquaporin channels , 2004, Proteins.

[29]  Rob Horsefield,et al.  High-resolution x-ray structure of human aquaporin 5 , 2008, Proceedings of the National Academy of Sciences.

[30]  Randy J Read,et al.  Electronic Reprint Biological Crystallography Likelihood-enhanced Fast Translation Functions Biological Crystallography Likelihood-enhanced Fast Translation Functions , 2022 .

[31]  B. Weinshenker,et al.  The spectrum of neuromyelitis optica , 2007, The Lancet Neurology.

[32]  Z. Otwinowski,et al.  Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[33]  P. Agre,et al.  Aquaporin-4 square array assembly: Opposing actions of M1 and M23 isoforms , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[34]  A. Verkman,et al.  Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides. , 2008, Bioorganic & medicinal chemistry.

[35]  E. Tajkhorshid,et al.  Molecular basis of proton blockage in aquaporins. , 2004, Structure.

[36]  Hjalmar Brismar,et al.  Identification of a molecular target for glutamate regulation of astrocyte water permeability , 2008, Glia.

[37]  Robert M Stroud,et al.  Structural basis of aquaporin inhibition by mercury. , 2007, Journal of molecular biology.

[38]  G. Manley,et al.  Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke , 2000, Nature Medicine.

[39]  A. Warshel,et al.  On the origin of the electrostatic barrier for proton transport in aquaporin , 2004, FEBS letters.

[40]  Z. Otwinowski,et al.  [20] Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[41]  Binghua Wu,et al.  Point mutations in the aromatic/arginine region in aquaporin 1 allow passage of urea, glycerol, ammonia, and protons. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[42]  B. Wallace,et al.  The pore dimensions of gramicidin A. , 1993, Biophysical journal.

[43]  T. Nakada,et al.  Identification of aquaporin 4 inhibitors using in vitro and in silico methods. , 2009, Bioorganic & medicinal chemistry.

[44]  K. Campbell,et al.  Dystrophin-Glycoprotein Complex: Post-translational Processing and Dystroglycan Function* 210 , 2003, The Journal of Biological Chemistry.

[45]  Y. Hiroaki,et al.  Acetazolamide reversibly inhibits water conduction by aquaporin-4. , 2009, Journal of structural biology.

[46]  Peter Agre,et al.  From structure to disease: the evolving tale of aquaporin biology , 2004, Nature Reviews Molecular Cell Biology.

[47]  Ian W. Davis,et al.  Structure validation by Cα geometry: ϕ,ψ and Cβ deviation , 2003, Proteins.

[48]  Jay Painter,et al.  TLSMD web server for the generation of multi-group TLS models , 2006 .

[49]  M. Wax,et al.  Regulation of Aquaporin-4 Water Channels by Phorbol Ester-dependent Protein Phosphorylation* , 1998, The Journal of Biological Chemistry.

[50]  T. Nakada,et al.  Identification of arylsulfonamides as Aquaporin 4 inhibitors. , 2007, Bioorganic & medicinal chemistry letters.

[51]  Robert M Stroud,et al.  The channel architecture of aquaporin 0 at a 2.2-A resolution. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[52]  Kevin Cowtan,et al.  research papers Acta Crystallographica Section D Biological , 2005 .