Joined the Department in 2009
- 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.
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.
- Shrestha, R, Lockless, SW, Sorg, JA. A Clostridium difficile alanine racemase affects spore germination and accommodates serine as a substrate. J. Biol. Chem. 2017;292 (25):10735-10742. doi: 10.1074/jbc.M117.791749. PubMed PMID:28487371 PubMed Central PMC5481577.
- Bian, X, Lockless, SW. Preparation To Minimize Buffer Mismatch in Isothermal Titration Calorimetry Experiments. Anal. Chem. 2016;88 (10):5549-53. doi: 10.1021/acs.analchem.6b01319. PubMed PMID:27092566 .
- Liu, S, Focke, PJ, Matulef, K, Bian, X, Moënne-Loccoz, P, Valiyaveetil, FI et al.. Ion-binding properties of a K+ channel selectivity filter in different conformations. Proc. Natl. Acad. Sci. U.S.A. 2015;112 (49):15096-100. doi: 10.1073/pnas.1510526112. PubMed PMID:26598654 PubMed Central PMC4679001.
- Beagle, SD, Lockless, SW. Microbiology: Electrical signalling goes bacterial. Nature. 2015;527 (7576):44-5. doi: 10.1038/nature15641. PubMed PMID:26503058 .
- Lockless, SW. Determinants of cation transport selectivity: Equilibrium binding and transport kinetics. J. Gen. Physiol. 2015;146 (1):3-13. doi: 10.1085/jgp.201511371. PubMed PMID:26078056 PubMed Central PMC4485025.
- Mukherjee, P, Banerjee, S, Wheeler, A, Ratliff, LA, Irigoyen, S, Garcia, LR et al.. Live imaging of inorganic phosphate in plants with cellular and subcellular resolution. Plant Physiol. 2015;167 (3):628-38. doi: 10.1104/pp.114.254003. PubMed PMID:25624397 PubMed Central PMC4348774.
- Huang, H, Levin, EJ, Liu, S, Bai, Y, Lockless, SW, Zhou, M et al.. Structure of a membrane-embedded prenyltransferase homologous to UBIAD1. PLoS Biol. 2014;12 (7):e1001911. doi: 10.1371/journal.pbio.1001911. PubMed PMID:25051182 PubMed Central PMC4106721.
- Liu, S, Lockless, SW. Equilibrium selectivity alone does not create K+-selective ion conduction in K+ channels. Nat Commun. 2013;4 :2746. doi: 10.1038/ncomms3746. PubMed PMID:24217508 .
- Liu, S, Bian, X, Lockless, SW. Preferential binding of K+ ions in the selectivity filter at equilibrium explains high selectivity of K+ channels. J. Gen. Physiol. 2012;140 (6):671-9. doi: 10.1085/jgp.201210855. PubMed PMID:23148260 PubMed Central PMC3514730.
- Lockless, SW, Muir, TW. Traceless protein splicing utilizing evolved split inteins. Proc. Natl. Acad. Sci. U.S.A. 2009;106 (27):10999-1004. doi: 10.1073/pnas.0902964106. PubMed PMID:19541616 PubMed Central PMC2708728.