TCB Publications - Abstract

Jing Li, Zhiyu Zhao, and Emad Tajkhorshid. Locking two rigid-body bundles in an outward-facing conformation: A general ion-coupling mechanism in LeuT-fold transporters. Scientific Reports, 9:19479, 2019. (PMC: PMC6925253)

LI2019-ET In secondary active transporters, electrochemical gradient of ions across the membrane fuels the ``uphill'' translocation of the substrate via the alternating- access mechanism. Despite recent significant experimental and computational studies, how driving ions couple to conformational dynamics of the transporters remains unclear. In the present study, we employ extended molecular dynamics (MD) simulations to study the impact of + binding on the structure and dynamics of a LeuT-fold, +-coupled secondary transporter (Mhp1) in its major conformational states, i.e., the outward-facing (OF) and inward-facing (IF) states, as well as on the transition between the states. Microseconds equilibrium MD simulations clearly illustrate that + stabilizes an OF conformation favorable for substrate association, by binding to a highly conserved site at the interface between the two helical bundles and restraining their relative position and motion in the OF state. Furthermore, ! a special-protocol time-dependent biased simulation for state transition estimates that + binding increases the barrier along the OF $\leftrightarrow$IF transition. These synergistic + binding effects allosterically couple the ion and substrate binding sites and modify the kinetics of state transition, which together increase the lifetime of an OF conformation with high affinity for substrate binding, thereby facilitating capturing the substrate efficiently from a low-concentration environment to fulfill the physiological function of the transporter. Based on the similarity between our findings for Mhp1 and experimental reports on LeuT, we propose that this model may represent a general +-coupling mechanism among LeuT-fold transporters deeply rooted in their common architecture.

Request Full Text

Request Paper

Full Name
Email Address
Type the number eight in the box