Heads of Laboratories
Electrical signals play many roles in the body. They control the pace of the heart, regulate the secretion of hormones into the bloodstream and transfer information from one cell to the next in the nervous system. Dr. MacKinnon’s research is aimed at understanding the physical and chemical principles underlying electricity in biology, particularly the passage of inorganic ions, such as potassium and chloride, across cell membranes.
Cells produce electrical signals using membrane proteins known as ion channels. These proteins catalyze the diffusion of inorganic ions down their electrochemical gradients across cell membranes. Because the diffusion is passive, ion channels would seem to be extraordinarily simple physical systems, and yet their remarkable properties enable the elaborate electrical machinery of life.
Ion channels, like enzymes, have specific substrates: Potassium, sodium, calcium and chloride channels permit only their namesake ions to diffuse through their pores. The ability of channels to discriminate among ions is called ion selectivity. Dr. MacKinnon’s laboratory has used mutational analysis to show that potassium channels are tetramers of identical subunits and that specific “signature sequence” amino acids are responsible for potassium selectivity. The signature sequence is conserved in all potassium channels throughout nature and forms a structural unit called the selectivity filter.
To understand how the selectivity filter conducts potassium ions so rapidly and selectively, the MacKinnon laboratory determined the x-ray structure of potassium channel KcsA at 2.0-Å resolution. The selectivity filter is a narrow, 12-Å-long segment of the pore lined with carbonyl oxygen atoms. These atoms act as surrogate water molecules, allowing potassium ions to shed their hydration shell and enter into the pore. Two potassium ions bind in the selectivity filter at once, usually with an intervening water molecule. Entry of a third potassium ion from one side of the filter is associated with potassium ion exit from the opposite side, resulting in rapid, efficient potassium ion conduction. Electrostatic repulsion between ions apparently prevents the potassium ions from binding too tightly, allowing high throughput in the setting of high selectivity.
Dr. MacKinnon’s laboratory has also studied the chloride channel. To understand how nature mediates anion selectivity, Dr. MacKinnon’s laboratory determined the atomic structure of a Cl- transport protein of the chloride channel family. Dr. MacKinnon has shown that although chloride channels are structured differently than potassium channels, they nevertheless utilize many of the same basic chemical principles to conduct Cl- ions.
A second area of investigation for the MacKinnon lab concerns how ion channels open and close in response to specific stimuli. In a process called gating, certain channels open when ligands bind (ligand-gated channels), while others open in response to membrane voltage (voltage-gated channels). The MacKinnon lab has determined the structures of both ligand- and voltage-gated K+ channels and has also identified a gating hinge that is common to both kinds of channels and enables α-helices to open the channel much in the way an aperture opens a camera’s lens. The ligand-gated channel has an additional structure that transfers a ligand’s binding energy into mechanical work to open the pore. The voltage-gated channel has an additional structure that converts the energy stored in the electric field across the membrane into pore-opening mechanical work. The voltage-gating mechanism underlies the electrical signals that are made by cells in the nervous system.
The MacKinnon lab’s most recent advance was the elucidation of the atomic structures of K+ channels from mammalian nerve cells. These first examples of eukaryotic membrane protein structures through recombinant expression open a new era in the study of membrane proteins from complex organisms.
Dr. MacKinnon received his B.A. in biochemistry from Brandeis University and his M.D. from Tufts University School of Medicine. He completed his medical residency at Beth Israel Hospital, Harvard Medical School, and postdoctoral work at Brandeis. He joined the faculty at Harvard Medical School before moving to Rockefeller in 1996.
Dr. MacKinnon is a member of the National Academy of Sciences. He is the recipient of numerous scientific awards, including the 2003 Nobel Prize in Chemistry, the 2003 Louisa Gross Horwitz Prize, the 2001 Gairdner Foundation International Award, the 2001 Perl-UNC Neuroscience Prize, the 2000 Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science and the 1999 Albert Lasker Basic Medical Research Award.
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