- B.S., 1997, Texas A&M University, Molecular and Cell Biology.
- Ph.D., 2002, UT Southwestern Medical Center, Molecular Biophysics.
- Postdoctoral research: The Rockefeller University.
Joined the department in 2009.
Lockless Lab Website
College Station, TX 77843-3474
Interdisciplinary Life Sciences Building
Interdisciplinary Life Sciences Building
|How is information integrated within and between proteins in signaling systems?
Ion channel gating and selectivity
All cells use selective transport of molecules across their membranes to maintain nutrient homeostasis and to support cellular signaling. Ion channels are found in all three domains of life and are used to modulate the cellular membrane potential and the proton-motive force. The largest family of channels is the tetrameric cation channels, including those for Na+, K+ and Ca2+ ions, which have two basic functional properties. They selectively conduct particular ions and they gate open or closed in response to stimuli. Together, these two processes control how rapidly the membrane potential changes, driving a wide-range of physiological processes. The overarching goal of this research project is to determine molecular mechanisms by which ion selectivity and gating are integrated into a concerted output, representing the sum total ion conduction across the membrane.
Mapping regulatory sites in networks of signaling and metabolic proteins
Genetics, site-directed mutagenesis and/or structure determination has been the primary means to identify regulatory molecules and their targets, but these approaches are each severely limited by practical considerations, e.g., observable phenotypes, functional assays, and protein expression. We overcame many of these problems by developing an approach to use compensatory mutations discovered within and between proteins in the exploding genome databases. The basic principle is that sites that influence each other are co-constrained throughout the evolution of the protein family. This approach not only identifies known allosteric sites in proteins, but also was used previously to predict novel regulatory sites that we validated as important for the protein’s function. When the same approach was employed to examine co-evolution between proteins, we identified proteins known to interact with one another in both stable and transient complexes. The overarching goal of this research project is to learn the rules that underlie the complex network of functional connections between signaling and metabolic proteins in cells, with one goal being to identify novel connections between cellular components.
- Mukherjee P, Banerjee S, Wheeler A, Ratliff LA, Irigoyen S, Garcia LR, Lockless SW & Versaw WK (2015) Live imaging of inorganic phosphate in plants with cellular and subcellular resolution. Plant Physiol 167:628-38 Full text
- Huang H, Levin EJ, Liu S, Bai Y, Lockless SW & Zhou M (2014) Structure of a membrane-embedded prenyltransferase homologous to UBIAD1. PLoS Biol 12:e1001911 Full text
- Liu S & Lockless SW (2013) Equilibrium selectivity alone does not create K+-selective ion conduction in K+ channels. Nat Commun 4:2746 Full text
- Liu S, Bian X & Lockless SW (2012) Preferential binding of K+ ions in the selectivity filter at equilibrium explains high selectivity of K+ channels. J Gen Physiol 140:671-9 Full text
- Lockless SW & Muir TW (2009) Traceless protein splicing utilizing evolved split inteins. Proc Natl Acad Sci U S A 106:10999-1004 Full text
- Lockless SW, Zhou M & MacKinnon R (2007) Structural and thermodynamic properties of selective ion binding in a K+ channel. PLoS Biol 5:e121 Full text
- Socolich M, Lockless SW, Russ WP, Lee H, Gardner KH & Ranganathan R (2005) Evolutionary information for specifying a protein fold. Nature 437:512-8 Full text
- Vergani P, Lockless SW, Nairn AC & Gadsby DC (2005) CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains. Nature 433:876-80 Full text
- Hatley ME, Lockless SW, Gibson SK, Gilman AG & Ranganathan R (2003) Allosteric determinants in guanine nucleotide-binding proteins. Proc Natl Acad Sci U S A 100:14445-50 Full text
- Süel GM, Lockless SW, Wall MA & Ranganathan R (2003) Evolutionarily conserved networks of residues mediate allosteric communication in proteins. Nat Struct Biol 10:59-69 Full text