Lipid Composition Modulates the Water Transport Function of Aquaporin Z By Altering Its Structural Dynamics

Aquaporins (AQPs) are an important class of intrinsic membrane proteins that mediate passive bidirectional water transport across cell membranes and are essential for many cellular processes. The rate of water transport mediated by AQPs varies in different membrane environments, highlighting the direct effects of the membrane composition on AQP function. How lipids in the membrane directly regulate water transport is unknown. The underpinning basis for membrane-effects on transporter function must involve a modulation of protein dynamics. In this study, we describe the dynamics and water transport of E. coli aquaporin Z (AqpZ) embedded in 3 different membrane-mimetic nanodiscs (DOPC, 3:1 DOPC: DOPG and E. coli polar lipid extracts) using amide hydrogen/deuterium exchange mass spectrometry (HDXMS). Our results revealed that membrane composition alters dynamics as read by HDXMS and this modulates water transport function of AqpZ. Correlation of AqpZ dynamics with water transport shows a bell-shaped curve wherein higher dynamics increases water transport up to a certain limit, after which it inhibits water transport. This indicates that lipids can function as critical allosteric regulators of water transport across AqpZ through a fine balance between stabilization and fluidity. This offers a handle to program water permeability of AqpZ by systematic alteration of protein dynamics in a membrane composition dependent manner. Our findings thus, revealed a novel lipid-mediated allosteric mechanism of AqpZ which has tremendous implications on cellular osmoregulation and selection of optimal membrane matrix materials for fabrication of highest water permeable AQP biomimetic membranes for desalination and other applications.