Opening the TRPML gates

Abstract

The intracellular TRPML channels have multiple biological roles, but the physiological stimuli that open them remained unknown. In a previous issue of Chemistry & Biology, Grimm et al. report a high-throughput chemical screen that identified a plethora of selective activators of TRPML3 that should open the way to fully characterize these channels and their physiological roles.

Figure 1. Predicted Topology of TRPML3 and Its Pore Structure

TRPML3 is predicted to have six transmembrane domains with cytoplasmic C and N termini and a large extracytosolic loop between transmembrane domains 1 and 2 that resides in the lumen of intracellular organelles or extracellularly when TRPML3 is in the plasma membrane. Shown are the position of His252, -273, and -283 that regulate TRPML3 activity by H⁺ and Na⁺ and the predicted structure of the TRPML3 pore. The position of the proline mutated in the varitint-waddler mouse (blue) and the pore aspartates (red, green) are also shown. The pore model was created by SWISS-MODEL server’s alignment interface, using the KcsA potassium channel as template. A TRPML3 tetramer was created by aligning the TRPML3 model with the KcsA tetramer using PyMol, and the figure was rendered with the same program. We are indebted to Dr. Michael Dorwart, UT Southwestern Medical Center, for help with modeling the TRPML3 pore.