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Featured Student and Faculty Member:

BCBC Programs Featured Graduate Student:

Momei Zhou

Momei Zhou, Cellular, Molecular and Microbial Biology Graduate Student (Ph.D.)

"This program offers a good environment for studying, that means people are close with each other here and as a student, you always get enough attention from your PI and also different input from other professors in the program.  Plus, Missoula is such a great small town for international student like myself...people here are so friendly...And not to mention the great outdoor entertainment in town or within a short drive. This is a great place to live!"  

Momei is from Chengdu, Sichuan, P.R. China and comes to UM from the Sichuan Agricultrual University in Sichuan, China.  She is currently working in Dr. Ryckman's lab on her Ph.D.  In her free time she enjoys hiking, watching movies or playing pool with friends.  

Research Focus: Functions and intra-strain diversity of human cytomegalovirus envelope glycoproteins: Characterization of the role of a viral glycoprotein gO during human cytomegalovirus cell-type dependent entry.

Facutly Advisor: Dr. Brent Ryckman

Entry of all herpesvirus requires interaction between fusion glycoprotein B (gB) and the regulatory glycoprotein complex gH/gL. Human Cytomegalovirus (HCMV) gH/gL can either be bound by gO or a set of glycoprotein UL128-131. Data indicate that gH/gL/gO serves the gB-regulation function for entry into all cell types, whereas gH/gL/UL128-131 provides a distinct receptor-binding function for entry into some cell types but not the others.  gO is a very diverse protein encoded by the virus, and the specific role of gO is unclear. In our lab, we study the function of gO by comparative studies of gO isoforms. My recent work showed that the ratio of these distinct gH/gL complexes on the virion envelope varies widely among strains of HCMV.  That stains of HCMV would differ in this manner was not appreciated.  Ongoing research is trying to elucidate why strains differ (i.e. genetic differences between strains, how the cell type (e.g., epithelial, endothelial, fibroblasts etc) might influence assembly of the virion envelope, and the significance the observed differences in the infection characteristics of HCMV.

Recent publication: Zhou M, Yu Q, Wechsler A, Ryckman BJ. (2013) Comparative Analysis of gO Isoforms Reveals that Strains of Human Cytomegalovirus Differ in the Ratio of gH/gL/gO and gH/gL/UL128-131 in the Virion Envelope.  J. Virol.  87(17): 9680-9690

Conferences and Presentations: International Herpes Virus Workshop, 2012 and 2013; BCBC Interdisciplinary Graduate Recruitment Weekend Presentation, March 2014.

BCBC Programs Featured Faculty Member:

Brent Ryckman

Brent Ryckman, Professor of Cellular, Molecular and Microbial Biology & Biophysics and Biochemistry

"UM is home to a supportive group of world-class scientists, and Missoula is a vibrant little city in the midst of spectacular natural beauty.  This means that I can spend a full day in the lab interacting with excellent colleagues and students, and then ride trials in the evening, all without being in my car."

Dr. Ryckman is an Associate Professor of Cellular, Molecular and Microbial Biology and Biophysics and Biochemistry.  He earned his Ph.D. from University of Iowa, and currently is mentoring 2 graduate students.  In his free time Brent is a bicyclist, dog owner, guitar player, and rock climber by choice. Backyard farmer, Food Co-op’er and yogi by accident.

Research focus: Functions and genetic diversity of HCMV envelope proteins that mediate entry and influence cellular tropism.

Our research focuses on aspects of how human cytomegalovirus (HCMV) initiates infection of different types of cells in the human body. HCMV is a herpesvirus that infects up to 90% of human populations. Like all herpesviruses, HCMV establishes latency – reactivation cycles, which can persist for the life of the host. In general, HCMV infections are well controlled by a robust host immune response. However, the virus may be transmitted across the placenta and infect the immune-naive fetus, which can result in extensive damage to the sensitive, still developing nervous system. Also, immunocompromised HIV/AIDS patients experience frequent HCMV reactivations, with common manifestations in the gastrointestinal tract, lungs, nervous system and retina, and in transplant recipients receiving immunosuppressive anti-rejection, HCMV reactivations are highly correlated with increased rates of graft failure. The pleomorphic manifestation of HCMV pathology correlates with a very broad cellular tropism, which in turn correlates with a complex array of viral surface proteins, and genetic diversity.

Herpesvirus entry and tropism have been best studied for herpes simplex virus (HSV) and Epstein-Barr virus (EBV). The emerging picture is that herpesvirus entry into all cells requires membrane fusion driven by the fusion protein gB, and the regulatory protein gH/gL. The exact mechanism of how gH/gL regulates gB-fusion activity is not clear, but likely involves interactions with cell surface molecules as receptors. HCMV has a number of other proteins that bind to the ectodomain of gH/gL and modify its function. The UL128, UL130, and UL131 proteins bind to gH/gL to form a pentameric complex, gH/gL/UL128-131, which seems to act as a receptor-binding complex necessary for entry into specific cell types, such as endothelial and epithelial cells. However this complex does not appear able to fulfill the “core” entry function of regulating gB. Instead, this function appears to be performed by a complex of gH/gL bound by gO. The exact role of gO has been a complete mystery since its discovery more than 15 years ago. But the fact that all primate and non-primate CMVs encode a gO homologue, and the fact that all gO null CMVs analyzed have been severely impaired indicate that gO is of fundamental importance to CMV biology. The function of gO is perplexing since, 1) in vitro cell-cell fusion experiments showed that gH/gL alone (not bound by either gO or UL128-131) can participate with gB in membrane fusion, and 2) gO is one of the more diverse proteins encoded by HCMV, with at least 8 isoforms differing by 10-30% of amino acids. A major focus of the ongoing research in the sponsor’s laboratory is the function of gO, and the significance of the diversity. We use a variety of approaches ranging from protein biochemistry to phylogenetics. More recently, we are developing approaches to address the mechanism by which gH/gL regulates gB by exploiting the fact that HCMV has two “forms” of gH/gL that appear to be functionally distinct in this respect.

Current research funding: National Institutes of Health, NIAID: Functional Diversity of the HCMV Glycoprotein O and Its Role in Viral Tropism, 1R01AI097274-01A1.

Recent publications:

Zhou M, Yu Q, Wechsler A, Ryckman B.J. (2013) Comparative analysis of gO Isoforms reveals that strains of human cytomegalovirus differ in the ratio of gH/gL/gO and gH/gL/UL128-131 in the virion envelope. Journal of Virology 87(17):9680-90.

Wille PT, Wisner TW, Ryckman B, Johnson DC. (2013) Human cytomegalovirus (HCMV) glycoprotein gB promotes virus entry in trans acting as the viral fusion protein rather than as a receptor-binding protein. MBio. 4(3):e00332-13.

Saccoccio, F., A. Sauer, A., X. Cui, A. Armstrong, E.E. Habib, D. Johnson, B. Ryckman, A. Klingelhutz, S.P. Adler, and M.A. McVoy. (2011) Peptides from Cytomegalovirus UL130 and UL131 Proteins induce high titer antibodies that block viral Entry into Mucosal Epithelial Cells. Vaccine. 29(15)2705-2711. PMCID: PMC3084484

Ryckman, B.J., M.C. Chase, and D.C. Johnson. (2010) Human cytomegalovirus TR strain glycoprotein O acts as a chaperone promoting gH/gL incorporation into virions but is not present in virions. J. Virol. 84(5):2597-2609. PMCID: PMC2820934

Previously Featured Students and Faculty Members:

Levi J. McClelland, Biochemistry & Biophysics Graduate Student (Ph.D.)

Levi McClelland

"This is a great environment to live and work in and I have been fortunate to meet many great friends."

Levi is from Slippery Rock, PA and comes to UM from Slippery Rock University.  He is currently working in Dr. Bowler's lab on his Ph.D.  In his free time he enjoys recreating in Montana's great outdoors with his pup, Barley.

Research Focus: Cytochrome c: Residue effects on and regluation of protein dynamics

Facutly Advisor: Dr. Bruce Bowler

The use of thermodynamic and kinetic techniques to study conformational changes of proteins. Specifically, we make use of iso-1-cytochrome c to study the mechanisms in regulating conformational change, which contribute to protein function.  Further we investigate contribution of residues to structure and relate our results to protein function including electron transfer and peroxidase activity, both of which are functions that cytochrome c undergoes during cellular energy production and the beginning steps of the intrinsic pathway of apoptosis, respectively.

Recent publication: McClelland, L. J., Mou, T. C., Jeakins-Cooley, M. E., Sprang, S. R. and Bowler, B. E. (2013) Structure of a mitochondrial cytochrome c conformer competent for peroxidase activity, submitted for publication.

Conferences: CBSD CoBRE Retreat 2012, 2013; NORM 2012, 2013; Biophysical Society 2013; MAS Spring 2013; Spring ACS (MT) 2013; UM Graduate Conference 2011-2013; ICBIC 15, 2011

Bruce Bowler, Professor of Biochemistry and Biophysics

Bruce Bowler

"I love the collaborative friendly environment of not just the research community at UM, but the Missoula community as a whole."

Dr. Bowler is the Biochemistry Graduate Program Director.  He earned his Ph.D. from MIT, and currently is working with 3 graduate students.  In his free time Bruce enjoys hiking with his Portuguese Water Dogs and singing tenor in the Missoula Symphony Chorale.

Research focus: Structural Studies on Alternate Conformers of Cytochrome c Required for Apoptosis (Programmed Cell Death)

The heme crevice loop of cytochrome c encloses one surface of the heme cofactor.  The heme is essential for both the electron transport and apoptotic functions of this protein. The heme crevice loop is the most highly conserved segment of the sequence of cytochrome c with 13 of 16 amino acids identical between yeast and humans. It is clearly highly evolved to carry out the two functions of the protein. Levi and I are collaborating with the Sprang and Ross labs to dissect the role of particular amino acids in the heme crevice loop in controlling access of cytochrome c to alternate conformers needed for the peroxidation of the mitochondrial membrane lipid, cardiolipin, in the early stages of apoptosis. We have just submitted a manuscript which describes a new structural form of the cytochrome c made possible by mutation of a residue in the heme crevice loop. This mutation also increases the peroxidase activity of the protein.

Current research funding: National Science Foundation, NSF: Gatekeeper Residues Control Peroxidase Activity of Cytochrome c in Apoptosis

The structure-function paradigm, which indicates that proteins have a unique structure designed for a single function, dominates biochemistry textbooks. Recent work indicates that many proteins can access more than one structure allowing them to carry out multiple functions. Cytochrome c is involved in both the electron transport chain, the primary energy storage pathway in aerobic organisms, and in apoptosis (programmed cell death) a key process in the growth and development of higher organisms such as mammals. This research will provide a molecular level understanding of how the transition between the two structures needed to carry out these two functions is controlled in cytochrome c.

Recent publications:

McClelland, L. J., Mou, T. C., Jeakins-Cooley, M. E., Sprang, S. R. and Bowler, B. E. (2013) Structure of a mitochondrial cytochrome c conformer competent for peroxidase activity, submitted for publication.

Cherney, M. M., Junior, C. C., Bergquist, B. B. and Bowler, B. E. (2013) Dynamics of the His79-heme alkaline transition of yeast iso-1-cytochrome c probed by conformationally gated electron transfer with Co(II)bis(terpyridine). J. Am. Chem. Soc. 135, 12772-12782. doi:10.1021/ja405725f

Cherney, M. M., Junior, C. and Bowler, B. E. (2013). Mutation of trimethyllysine-72 to alanine enhances His79-heme mediated dynamics of iso-1-cytochrome c. Biochemistry 52, 837-846. doi:10.1021/bi301599g

Bandi, S. and Bowler, B. E. (2013). A cytochrome c electron transfer switch modulated by heme ligation and isomerization of a peptidyl-prolyl bond. Biopolymers, Peptide Science 100, 114-124. doi:10.1002/bip.22164/abstract

Graphics, Design, & Layout by Spectral Fusion Designs, 2013.