H. Ronald Kaback, M.D.

Work Address:
Los Angeles, CA 90095 MRL
Los Angeles, CA 90095

Distinguished Professor, Physiology
Professor, Microbiology, Immunology & Molecular Genetics
Member, Brain Research Institute, Molecular, Cellular & Integrative Physiology GPB Home Area
Research Interests
The lactose permease of Escherichia coli (LacY), a particularly well-studied paradigm for ion gradient driven active transport proteins, is solely responsible for all translocation reactions catalyzed by the galactoside transport system in E. coli. Like many active transport proteins, LacY couples the free energy released from downhill translocation of protons in response to a proton electrochemical gradient to drive the energetically uphill stoichiometric accumulation of D-galactopyranosides. An X-ray structure of LacY has been solved in an inward-facing conformation, confirming many conclusions derived from various biochemical and biophysical studies. The molecule is composed of N- and C-terminal domains, each with six transmembrane helices, symmetrically positioned within the molecule, and many of the helices are irregularly shaped. A large internal water-filled cavity is exposed to the cytoplasm, and sugar is bound at the two-fold axis of symmetry at the apex of the hydrophilic cavity and in the approximate middle of the molecule. Access to the sugar-binding site is completely blocked from the outer side of the molecule. By combining a large body of experimental data derived from systematic studies of site-directed mutants, residues involved in substrate binding and proton translocation have been identified. Based on the functional properties of the mutants and the X-ray structure, a working model for the mechanism involving alternating access of the binding site to either side of the membrane has been postulated. Recent experimental results obtained using site-directed alkylation of cysteine-replacement mutants, isothermal calorimetry, site-directed fluorescence and spin labeling provide strong supporting evidence for the alternating access model.

H. Ronald Kaback has been a member of the faculty at UCLA since he joined the Depts. of Physiology and Microbiology, Immunology & Molecular Genetics, as well as the Molecular Biology Institute, in 1989 as a full professor. Dr. Kaback earned his B.S. at Haverford College and his M.D. at The Albert Einstein College of Medicine, where he also did an internship in Pediatrics. After a year as a graduate student, he became a Commissioned Officer in the USPHS at the NIH and subsequently became at Staff Associate. He then moved to the Roche Institute of Molecular Biology in Nutley, NJ where he later became Head of Biochemistry before coming to UCLA. He is a member of the National Academy of Science and is the recipient of many awards for his work.


A selected list of publications:

Zhou, Y. Guan, L. Kaback, H. R.   Opening and closing of the periplasmic gate in lactose permease, Proc Natl Acad Sci U S A, 2008; in press.
Nie, Y. Ermolova, N. Kaback, H. R.   Site-directed Alkylation of LacY: Effect of the Proton Electrochemical Gradient J Mol Biol, 2007; 374(2): 356-64.
Smirnova, I. Kasho, V. Choe, J. Y. Altenbach, C. Hubbell, W. L. Kaback, H. R.   Sugar binding induces an outward facing conformation of LacY Proc Natl Acad Sci U S A, 2007; 104: 16504-16509.
Guan, L. Mirza, O. Verner, G. Iwata, S. Kaback, H. R.   Structural determination of wild-type lactose permease Proc Natl Acad Sci U S A, 2007; 104(39): 15294-8.
Majumdar, D. S. Smirnova, I. Kasho, V. Nir, E. Kong, X. Weiss, S. Kaback, H. R.   Single-molecule FRET reveals sugar-induced conformational dynamics in LacY Proc Natl Acad Sci U S A, 2007; 104(31): 12640-12645.
Guan, L. Kaback, H. R.   Site-directed alkylation of cysteine to test solvent accessibility of membrane proteins Nat Protoc, 2007; 2(8): 2012-7.
Shimohata, N. Nagamori, S. Akiyama, Y. Kaback, H. R. Ito, K.   SecY alterations that impair membrane protein folding and generate a membrane stress J Cell Biol, 2007; 176(3): 307-17.
Smirnova, I. N. Kasho, V. N. Kaback, H. R.   Direct Sugar Binding to LacY Measured by Resonance Energy Transfer Biochemistry, 2006; 45(51): 15279-87.
Kaback, H. R. Dunten, R. Frillingos, S. Venkatesan, P. Kwaw, I. Zhang, W. Ermolova, N.   Site-directed alkylation and the alternating access model for LacY Proc Natl Acad Sci U S A, 2006; .
Guan, L. Kaback, H. R.   Lessons from Lactose Permease Annu Rev Biophys Biomol Struct, 2006; 35: 67-91.
Nie, Y. Smirnova, I. Kasho, V. Kaback, H. R.   Energetics of Ligand-induced Conformational Flexibility in the Lactose Permease of Escherichia coli J Biol Chem, 2006; 281(47): 35779-84.
Vadyvaloo, V. Smirnova, I. N. Kasho, V. N. Kaback, H. Ronald   Conservation of residues involved in sugar/H(+) symport by the sucrose permease of Escherichia coli relative to lactose permease J Mol Biol, 2006; 358(4): 1051-9.
Kasho, V. N. Smirnova, I. N. Kaback, H. R.   Sequence alignment and homology threading reveals prokaryotic and eukaryotic proteins similar to lactose permease J Mol Biol, 2006; 358(4): 1060-70.
Ermolova, N. Madhvani, R. V. Kaback, H. R.   Site-directed alkylation of cysteine replacements in the lactose permease of Escherichia coli: helices I, III, VI, and XI Biochemistry, 2006; 45(13): 4182-9.
Mirza, O. 2006)200251183Guan, L. Verner, G. Iwata, S. Kaback, H. R.   Structural evidence for induced fit and a mechanism for sugar/H(+) symport in LacY Embo J, 2006; 25: 1177-1183.
Guan, L. Smirnova, I. N. Verner, G. Nagamoni, S. Kaback, H. R.   Manipulating phospholipids for crystallization of a membrane transport protein Proc Natl Acad Sci U S A, 2006; 103(6): 1723-6.
Kaback, H. R.   Structure and mechanism of the lactose permease C R Biol, 2005; 328(6): 557-67.
Kaback, H. R   The Passion of the Permease, Biophysical and Structural Aspects of Bioenergetics, 2005; 359-373.
Ermolova, N. V. Smirnova, I. N. Kasho, V. N. Kaback, H. R.   Interhelical packing modulates conformational flexibility in the lactose permease of Escherichia coli Biochemistry, 2005; 44(21): 7669-77.
van Bloois, E. Nagamori, S. Koningstein, G. Ullers, R. S. Preuss, M. Oudega, B. Harms, N. Kaback, H. R. Herrmann, J. M. Luirink, J.   The Sec-independent function of Escherichia coli YidC is evolutionary-conserved and essential J Biol Chem, 2005; 280(13): 12996-3003.
Weinglass, A. B. Soskine, M. Vazquez-Ibar, J. L. Whitelegge, J. P. Faull, K. F. Kaback, H. R. Schuldiner, S.   Exploring the role of a unique carboxyl residue in EmrE by mass spectrometry J Biol Chem, 2005; 280(9): 7487-92.
Sun, J. Savva, C. G. Deaton, J. Kaback, H. R. Svrakic, M. Young, R. Holzenburg, A.   Asymmetric binding of membrane proteins to GroEL Arch Biochem Biophys, 2005; 434(2): 352-7.