Mechanism of gating and ion conductivity of a possible tetrameric pore in aquaporin-1.
While substrate permeation through monomeric pores of aquaporins is well characterized, little is known about the possible tetrameric pore. AQP1 has been suggested to function as an ion channel upon cGMP activation, although this idea has been controversial. Taking a theoretical and experimental approach, we demonstrate that the current might arise through the tetrameric pore and propose a plausible mechanism for conduction and gating. In response to simulated ion permeation, immediate hydration of the putative central pore was facilitated by moderate conformational changes of pore-lining residues. cGMP is found to interact with an unusually arginine-rich, cytoplasmic loop (loop D) facilitating its outward motion, which is hypothesized to trigger the opening of a cytoplasmic gate. Physiological analyses of wild-type AQP1 and a designed mutant in which two arginines of the gating loop are replaced by alanine provide experimental support for identifying a key component of the proposed mechanism.
Yu
Jin
J
Theoretical and Computational Biophysics Group, Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Yool
Andrea J
AJ
Schulten
Klaus
K
Tajkhorshid
Emad
E
D000595:Amino Acid Sequence; D051398:Aquaporin 1 / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry; D015640:Ion Channel Gating; D017136:Ion Transport; D008969:Molecular Sequence Data; D011485:Protein Binding
D051398:Aquaporin 1; D006152:Cyclic GMP