Ian C. Brett
B.S. College of Mount St. Vincent, 1996

4th Year PhD Student

Advisor: Steven O. Smith, Ph.D.

Department: Biochemistry & Cell Biology

Graduate Program: Biochemistry & Structural Biology

Abstract:

Title: The Role of the Transmembrane and Juxtamembrane Regions of Cytokine Receptors in Signal Transduction

Cytokine receptors such as the Epo receptor and the Tpo receptor are single pass transmembrane (TM) proteins that as monomers consist of an extracellular (EC) domain, a TM alpha helix, and an intracellular (IC) domain. Upon ligand binding, changes in EC domain position/structure are transmitted through the TM domain to the IC domain. This allows Jak2 activation and phosphorylation of tyrosine residues in the cytoplasmic domain of the receptor as well as Jak2 itself. This initiates a cascade of signal transduction resulting in the production of RBCs or platelets. Structural analysis of these proteins has typically focused solely on the EC domain where ligand binds because these hydrophilic domains are easily crystallized. Functional mechanisms have been proposed based on these structural constraints without structural knowledge of the remainder of the protein.

Research from our lab and others suggests that the transmembrane domain plays an important role in the functional mechanism of cytokine receptors. Data suggests that the TM domain not only mediates association of receptor monomers, but activation of the receptor dimer is dependent upon the rotational orientation of the TM domain. These constraints would change the proposed method of receptor activation. We think that the best way to elucidate the initiation of the intracellular signaling cascade is to study the structure of the entire protein. By using a combination of biophysical techniques including NMR we intend to solve the high-resolution solution structure of these transmembrane receptor proteins. This structural knowledge will aid us in proposing a general model for the activation of cytokine receptors and could facilitate the development of new pharmacotherapies for the treatment of erythropoietic diseases.

Publications:
(MSTP-supported publications indicated with an *)

Brett I, Werber J, Kilbourne ED. (2002) Rapid confirmation by RFLP of transfer to vaccine candidate reassortment viruses of the principal ‘high yield’ gene of influenza A viruses. J Virol Meth. 100:133-140.

Kilbourne ED, Smith C, Brett I, Pokorny BA, Johansson B, Cox N. (2002) The total influenza vaccine failure of 1947 revisited: Major intrasubtypic antigenic change can explain failure of vaccine in a post-World War II epidemic. Proc Nat Acad Sci. 99(16):10748-10752.

Brown ST, Brett I, Almenoff PL, Lesser M, Terrin M, Teirstein AS. (2003) Recovery of cell wall deficient organisms from blood does not distinguish between subjects with sarcoidosis and controls. Chest 123(2):413-7.

Johansson, BE and Brett, IC. (2003) Variation in divalent cation requirements of influenza A virus N2 neuraminidases. J Biochem. 134(2):345-352.

Kilbourne ED, Pokorny BA, Johansson B, Brett I, Milev Y, Matthews JT. (2004) Protection of mice with recombinant influenza virus neuraminidase. J Infect Dis. 189(3):459-61.

Noy A, Yahalom J, Zaretsky L, Brett I, Zelenetz AD. (2005) Gastric mucosa-associated lymphoid tissue detected by clonotypic polymerase chain reaction despite continuous pathologic remission induced by involved-field radiotherapy. J Clin Oncol. 23(16):3768-72.

Brett IC, Johansson BE. (2005) Immunization against Influenza A virus: Comparison of conventional inactivated, live-attenuated, and recombinant baculovirus produced purified hemagglutinin and neuraminidase vaccines in a murine model system. Virology. 339(2):273-80.

Brett IC, Johansson BE. (2006) Variation of divalent cation requirements of influenza A virus N1 neuraminidases. J Biochem. 136:439-447.

Johansson BE, Brett IC. (2006) An inactivated subvirion influenza A (H5N1) vaccine. NEJM. 354(25):2724-5. (Letter to the editor)

Johansson BE, Brett IC. (2007) Changing perspective on immunization against influenza. Vaccine. 25(16):3062-5.

Johansson BE, Brett IC. Recombinant influenza B virus HA and NA antigens administered in equivalent amounts are immunogenically equivalent and induce equivalent homotypic and broader heterovariant protection in mice than conventional and live influenza vaccines. Human Vaccine. 2008 Nov-Dec;4(6):420-4.

Johansson BE, Brett IC. (2009) Mouse models of influenza. Handbook on Immunosenescence: basic understanding and clinical applications. Fulop, T.; Franceschi, C.; Hirokawa, K.; Pawelec, G. (Eds.) Springer Science+Business Media BV.