Harold P. Erickson, Ph.D. (Johns Hopkins University)
James B. Duke Professor,
Department of Cell Biology
Programs: Cell and Molecular Biology, Structural Biology and Biophysics
412 Nanaline Duke Bldg., Box 3709
Duke University Medical Center
Durham, NC 27710
Cytoskeleton: It is now clear that the actin and microtubule cytoskeleton originated in bacteria. Our major research is on FtsZ, the bacterial tubulin homolog, which assembles into a contractile ring that divides the bacterium. We have studied FtsZ assembly in vitro, and found that it assembles into thin protofilaments (pfs). Dozens of these pfs are further clustered to form the contractile Z-ring in vivo.
Some important discoveries in the last ten years include:
• Reconstitution of Z rings in vitro. We provided FtsZ with a membrane tether, and found that when incorporated inside liposomes, FtsZ-mts can assemble Z rings without any other proteins.
• These reconstituted Z rings generate a constriction force on the membranes, again without any other proteins (no motor molecules).
• The constriction force is generated by a curved conformation of FtsZ-pfs generating a bending force on the membrane.
Important questions for the future are:
· How are FtsZ pfs arranged in the Z ring? We favor the ribbon model, where pfs are parallel and laterally associated into a ribbon. Many others in the field favor a scattered model, where pfs are more widely separated. We are exploring new electron microscopy (EM) methods to resolve the structure. We have also developed new tools to facilitate superresolution light microscopy (PALM).
· How does FtsZ treadmilling work? Our lab provided the first evidence that FtsZ treadmills, adding subunits at one end and losing them at the other (Redick J Bact 2005). This has now been confirmed in vitro and in vivo. We are developing theoretical models and experimental (EM) methods to determine the detailed mechanism of treadmilling.
· What is the structure of the septum in dividing bacteria? There is wide agreement that Gram-positive bacteria divide by ingression of a plate-like septum. Conventional EM suggests that Gram-negative bacteria have a shallower V-shaped constriction. We are revisiting this using novel fixatives and high-pressure freezing for thin section EM.
Irisin. We believe the irisin story is bunk. Irisin was proposed in 2012 as a novel myokine, secreted by muscle cells in response to exercise, it induces the transformation of white fat to brown fat. This inspired hopes of an exercise pill that might correct obesity and other metabolic disorders. We have argued that the original discovery was flawed in several respects (Erickson, Adipocyte, 2013), and that the 300+ published follow-up studies are based on flawed commercial antibodies (Albrecht et al, Sci Rep 2015). We are now developing new assays to determine if irisin exists in in the blood of humans, primates and other animals. We expect it does not, especially in humans whose FNDC5 gene has a mutated start codon.
Erickson HP. (2017) The discovery of the prokaryotic cytoskeleton: 25th anniversary. Mol Biol Cell. 1;28(3):357-358.
Chen Y, Porter K, Osawa M, Augustus AM, Milam SL, Joshi C, Osteryoung KW, Erickson HP. (2017) The Chloroplast Tubulin Homologs FtsZA and FtsZB from the Red Alga Galdieria sulphuraria Co-assemble into Dynamic Filaments. J Biol Chem.
Shah R, Ohashi T, Erickson HP, Oas TG. (2017) Spontaneous Unfolding-Refolding of Fibronectin Type III Domains Assayed by Thiol Exchange: Thermodynamic Stability Correlates With Rates of Unfolding Rather Than Holding. J Biol Chem. 20;292(3):955-966.
Suzuki A, Badger BL, Haase J, Ohashi T, Erickson HP, Salmon ED, Bloom K. (2016) How the kinetochore couples microtubule force and centromere stretch to move chromosomes. Nat Cell Biol. 18(4):382-92.
Mansour RG, Stamper L, Jaeger F, McGuire E, Fouda G, Amos J, Barbas K, Ohashi T, Alam SM, Erickson H, Permar SR. (2016) The Presence and Anti-HIV-1 Function of Tenascin C in Breast Milk and Genital Fluids. PLoS One. 16;11(5):e0155261.
Housman M, Milam SL, Moore DA, Osawa M, Erickson HP. (2016) FtsZ Protofilament Curvature Is the Opposite of Tubulin Rings. Biochemistry. 26;55(29):4085-91.
Moore DA, Whatley ZN, Joshi CP, Osawa M, Erickson HP. (2016) Probing for Binding Regions of the FtsZ Protein Surface through Site-Directed Insertions: Discovery of Fully Functional FtsZ-Fluorescent Proteins. J Bacteriol. 13;199(1).
Erickson HP. (2016) Protein unfolding under isometric tension-what force can integrins generate, and can it unfold FNIII domains? Curr Opin Struct Biol. 27;42:98-105.
Bisson-Filho AW, Discola KF, Castellen P, Blasios V, Martins A, Sforça ML, Garcia W, Zeri AC, Erickson HP, Dessen A, Gueiros-Filho FJ (2015) FtsZ filament capping by MciZ, a developmental regulator of bacterial division. Proc Natl Acad Sci USA 112(17):E2130-8.
Albrecht E, Norheim F, Thiede B, Holen T, Ohashi T, Schering L, Lee S, Brenmoehl J, Thomas S, Drevon CA, Erickson HP, Maak S (2015) Irisin - a myth rather than an exercise-inducible myokine. Sci Rep 5:8889