New paper on TREK channels

This paper came out of a collaboration instigated by my former fellow Sarosh Fatakia.  We applied our method using mutual information (see here and here) to a family of potassium channels known as TREK channels.

Structural models of TREK channels and their gating mechanism

A.L. Milac, A. Anishkin, S.N. Fatakia, C.C. Chow, S. Sukharev, and H. R. Guy

Mechanosensitive TReK channels belong to the family of K2p channels, a family of widely distributed, well-modulated channels that uniquely have two similar or identical subunits, each with two TM1-p-TM2 motifs. Our goal is to build viable structural models of TReK channels, as representatives of K2p channels family. The structures available to be used as templates belong to the 2TM channels superfamily. These have low sequence similarity and different structural features: four symmetrically arranged subunits, each having one TM1-p-TM2 motif. Our model building strategy used two subunits of the template (KcsA) to build one subunit of the target (TREK-1).  Our models of the closed channel were adjusted to differ substantially from those of the template, e.g., TM2 of the second repeat is near the axis of the pore whereas TM2 of the first repeat is far from the axis.  Segments linking the two repeats and immediately following the last TM segment were modeled ab initio as α-helices based on helical periodicities of hydrophobic and hydrophilic residues, highly conserved and poorly conserved residues and statistically related positions from multiple sequence alignments. The models were further refined by 2-fold symmetry-constrained MD simulations using a protocol we developed previously. We also built models of the open state and suggest a possible tension-activated gating mechanism characterized by helical motion with 2-fold symmetry. Our models are consistent with deletion/truncation mutagenesis and thermodynamic analysis of gating described in the accompanying paper.



addendum: link fixed


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