H. Ron Kaback
Professor H. Ronald Kaback has been a member of the faculty at UCLA since he joined the Department of Physiology and Microbiology, Immunology & Molecular Genetics, as well as the Molecular Biology Institute. Dr.. Kaback earned his B.S. at Haverford College in 1958 and his M.D. at The Albert Einstein College of Medicine in 1962; he interned at the Bronx Municipal Hospital Center in Pediatrics and did postdoctoral research at Einstein. In 1964, he then became a Commissioned Officer in the US Public Health Service at the National Institutes of Health in what was then the National Heart Institute in the laboratory of E.R. Stadtman and subsequently became a Staff Associate. In 1970, he moved to the Roche Institute of Molecular Biology in Nutley, NJ where he later became Head of Biochemistry before coming to UCLA in 1989 as an Investigator of the Howard Hughes Medical Institute. He is a member of the National Academy of Science and the American Academy of Arts and Sciences and a Fellow of the American Academy of Microbiology, the American Biophysical Society and the American Association for the Advancement of Science. He is also the recipient of many awards for his work.
Adventures in Serendipity:
Ron Kaback describes his life and his development as a scientist, both of which involve numerous serendipitous events, in a book -- Thus, the title Adventures in Serendipity. For readers who may not be scientists, most of the science described can be scanned superficially or skipped altogether, as an equally important aspect of the book is to emphasize that there is more to science than just science. Also to be emphasized, if a good fairy appears with a magic wand and offers you the choice between being smart or being lucky, always pick lucky. But put your heart and soul into it whatever you do.
Although many associate my name with the lactose permease (LacY) and cysteine-scanning mutagenesis, I believe my major contribution is probably the invention of membrane vesicles as a model system in which to study transport. In so-called 'primary' active transport, the energy of ATP hydrolysis is utilized directly to drive solute transport against a concentration gradient. In contrast, with 'secondary' active transport, solute accumulation or efflus against a concentration gradient is driven by the electrochemical potential difference of protons or sodium across the membrane (i.e., Δμ̃H+ or Δμ̃Na+).
This type of transport is catalyzed by many of the members of the Major Facilitator Super Family (MFS), a huge family of membrane transport proteins responsible for the transport of sugars, amino acids, peptides, drugs, neurotransmitters and many other substrates. The MFS comprised 25% of all transport protein. Like channels and ATP Binding Cassette (ABC) transporters, ion gradient-coupled membrane transporter proteins are highly relevant to human physiology and disease (e.g. depression, epilephy, diabetes, multi drug resistance). Also of note, at least two of the most widely prescribed drugs in the world [serotonin selective re uptake inhibitors (SSRIs) and gastric proton pump inhibitors (PPIs)], are targeted to membrane transport proteins. Most transport proteins fall into families that appear to have similar secondary structures based on gene sequencing and hydropathy profiling. Thus, it seem likely that tertiary structures and mechanisms have been preserved during evolution.
We aim to understand the detailed mechanism of lactose/H+ symport (co-transport) by the lactose premease of Escherichia coli (LacY) as a paradigm for membrane transport proteins in general. Galactoside transport by LacY is coupled stoichiometrically with transport of a single H+, and sugar binding requires protonation of LacY (i.e., galactoside/H+ symport). X-ray structures of wild-type LacY, as well as a conformationally restricted mutant and a complete library of single-Cys and many other mutants, have provided critical information regarding the structure and mechanism of LacY. The protein contains two jydrophilic internal cavity open to the cytoplasmic side only. Thus, the sugar-binding site located at the apex of the cavity is inaccessible from the periplasmic side. However, LacY is conformationally very flexible, and during turnover, the inward-facing cavity closes with opening of a complementary outward-facing cavity so that the binding site is alternatively accessible to either side o the membrane (i.e., the alternating access model). Although essential, x-ray structure represent do not provide dynamic information, and we are just beginning to gain insight into the symport mechanism at the atomic level from biochemical/spectroscopic studies, which provide dynamic information.
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