Valentina Perissi Promotion

June 4th, 2018in Departmental News

The Department would like to congratulate Dr. Valentina Perissi on her recent promotion to AssociateVP2017Professor of Biochemistry. This is a well-deserved honor. Please read more about the ongoing research in the Perissi lab.

Research Discoveries: Jello in Your Fat

A new study from the Layne lab “Aortic carboxypeptidase-like protein enhances adipose tissue stromal progenitor differentiation into myofibroblasts and is upregulated in fibrotic white adipose tissuepicrofat” was recently published in PLoS One. This research identified a new pathway regulating of adipose tissue differentiation and fibrotic remodeling. First author and graduate student Mike Jager, along with collaborators in the Farmer and Fried labs determimed that the secreted protein Aortic Carboxypeptidase-like Protein (ACLP) repressed the differentiation of mouse and human adipocyte progenitors and was upregulated in fibrotic adipose tissue. ACLP was co-expressed with collagens in the adipose tissue and indicate that ACLP is a novel regulator of adipose progenitors and fibrosis.

Matthew Layne receives GMS Faculty Recognition Award

June 1st, 2018in Departmental News

The winner of the 2018 Graduate Medical Sciences Faculty Recognition Award was announced yesterday at John McCahan Medical Education Day (May 30, 2018) . A faculty member who epitomizes this award that recognizes those who go above and beyond expectations for our teaching mission, our own Dr. Matthew Layne is this year’s honoree! Dr. Layne is a premier educator and one so very deserving of this honor! Congratulations Dr. Layne!

New research discoveries: glutamine metabolism controls breast cancer

April 23rd, 2018in Departmental News, Research News

glutamineA new study from Dr. Varelas’ group has revealed important insights into the molecular mechanisms that control breast cancer cell growth. Their report, recently published in EMBO Reports, describes a role for the transcriptional regulators TAZ and YAP in driving oncogenic growth by promoting the expression of enzymes that control glutamine metabolism. Aggressive breast cancer cells are known to rely on an exogenous source of the amino acid glutamine for efficient growth. This study shows that TAZ and YAP contribute to glutamine dependence and reveals that cells with increased TAZ/YAP activity are vulnerable to compounds that inhibit key glutamine-utilizing enzymes, such as transaminases. Assessing TAZ/YAP activity in breast cancers may therefore offer a means for predicting response to targeted therapies with transaminase inhibitors, representing an exciting avenue for cancer therapy.

Research discoveries: new genetic form of connective tissue disease

February 21st, 2018in Departmental News, Research News

A multi-laboratory collaboration has lead to the identification of genetic changes in the human AEBP1 gene, which encodes the Aortic Carboxypeptidase-like Protein (ACLP), that leads to defective collagen assembly and a variant of Ehlers Danlos Syndrome (EDS). This research was published in the American Journal of Human Genetics.

Researchers from the Layne laboratory, including students Rose Zhao, Kathleen Tumelty, and William Monis, along with researchers from the Mayo Clinic, King Faisal Hospital in Saudi Arabia, and at the Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health have identified families with AEBP1 genetic mutations resulting in a constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of EDS. This study also showed that the ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that biallelic pathogenic variants in AEBP1 are the cause of this autosomal recessive EDS subtype.

Blackburn PR, Xu Z, Tumelty KE, Zhao RW, Monis WJ, Harris KG, Gass JM, Cousin MA, Boczek NJ, Mitkov MV, Cappel MA, Francomano CA, Parisi JE, Klee EW, Faqeih E, Alkuraya FS, Layne MD, McDonnell NB, Atwal PS. Biallelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome. Am J Human Genetics 2018, in press.

Research discoveries: glycoprotein glycosylation

New research papers from the Zaia laboratory have established novel strategies for analyzing glycans and glycopeptides.

Glycomics and glycoproteomics analyses by mass spectrometry require efficient front-end separation methods to enable deep characterization of heterogeneous glycoform populations. Chromatography methods azaiapaperre generally limited in their ability to resolve glycoforms using mobile phases that are compatible with online liquid chromatography-mass spectrometry (LC-MS). The adoption of capillary electrophoresis-mass spectrometry methods (CE-MS) for glycomics and glycoproteomics is limited by the lack of convenient interfaces for coupling the CE devices to mass spectrometers. Here, we describe the application of a microfluidics-based CE-MS system for analysis of released glycans, glycopeptides and monosaccharides. We demonstrate a single CE method for analysis three different modalities, thus contributing to comprehensive glycoproteomics analyses. In addition, we explored compatible sample derivatization methods. We used glycan TMT-labeling to improve electrophoretic migration and enable multiplexed quantitation by tandem MS. We used sialic acid linkage-specific derivatization methods to improve separation and the level of information obtained from a single analytical step. Capillary electrophoresis greatly improved glycoform separation for both released glycans and glycopeptides over that reported for chromatography modes more frequently employed for such analyses. Overall, the CE-MS method described here enables rapid setup and analysis of glycans and glycopeptides using mass spectrometry

To learn more:

  1. Khatri, K.; Klein, J. A.; Zaia, J. Use of an informed search space maximizes confidence of site-specific assignment of glycoprotein glycosylation. Anal Bioanal Chem 2017, 409, 607-618. Pubmed Link
  2. Khatri, K.; Klein, J. A.; Haserick, J.; Leon, D. R.; Costello, C. E.; McComb, M. E.; Zaia, J. Microfluidic capillary electrophoresis-mass spectrometry for analysis of monosaccharides, oligosaccharides and glycopeptides. Anal. Chem. 2017, 89, 6645-6655. Pubmed Link

 

Inhibiting G protein signaling and disease

November 19th, 2017in Departmental News, Research News
A recent publication from Garcia-Marcos laboratory in PNAS shows how to target an atypical mechanism of heterotrimeric G protein signaling linked to different human diseases by rationally designing a synthetic protein inhibitor. 
 
Dysregulation of signaling via heterotrimeric G proteins leads to pathogenesis. Thus, developing an efficient armamentarium to study G protein regulation is crucial for understanding the molecular basis of disease. The classical view of G protein activation as an exclusive function of G protein-coupled receptors has been challenged by the discovery of nonreceptor G protein activators. Dysregulation of a family of such nonreceptor activators has been linked to human disorders like cancer or birth defects, but the underlying mechanisms remain poorly understood due to the lack of experimental tools. The Garcia-Marcos laboratory used protein engineering to rationally design a genetically encoded inhibitor of these G protein activators, called “GBA proteins” for G(alpha) Binding and Activating, and demonstrated its usefulness to block aberrant signaling in cancer cells and abrogate developmental malformations in animal embryos. The engineering consisted of transforming a natural G protein into a synthetic one that binds tightly to GBA proteins but cannot bind to any other G protein binding partner or regulator.

Citation: Specific inhibition of GPCR-independent G protein signaling by a rationally engineered protein.

Leyme A, Marivin A, Maziarz M, DiGiacomo V, Papakonstantinou MP, Patel PP, Blanco-Canosa JB, Walawalkar IA, Rodriguez-Davila G, Dominguez I, Garcia-Marcos M. Proc Natl Acad Sci U S A. 2017 Nov 13. pii: 201707992. doi: 10.1073/pnas.1707992114. [Epub ahead of print] PMID: 29133411

https://www.ncbi.nlm.nih.gov/pubmed/29133411

Center for Network Systems Biology Grand Opening

October 3rd, 2017in Departmental News, Research News

Andrew Emili Heads New Center for Network Systems Biology
from BU Today
Andrew Emili, with a joint appointment as a professor in the MED biochemistry department and the CAS biology department, is the director of the new University-wide Center for Network Systems Biology. Photo by Cydney Scott

As a McGill University undergraduate, Andrew Emili earned money putting together IKEA furniture. The assembly instructions may have stymied his customers, but at least instructions existed. That’s more than can be said for Emili’s current challenge: mapping the network of interactions between the tens of thousands of proteins encoded in the human genome.

“It’s like trying to put together IKEA furniture when you’ve lost the assembly instructions,” says Emili, a molecular systems biologist who arrived at Boston University from the University of Toronto in July. “You see bolts, you see holes, and you know the relationship between the two, but not which ones go where.”

Emili, jointly appointed to the School of Medicine biochemistry department and the College of Arts & Sciences biology department, is director of the new University-wide Center for Network Systems Biology (CNSB).

Human health and development depend on the network of protein interactions, he says. Yet despite rapid advances in genomics, scientists know little about how these interactions work and how faulty interactions lead to disease. He uses proteomics, the study of the protein products of genes, and mass spectrometry, a tool that can separate individual proteins from their connections, as well as bioinformatics and other molecular genetic and genomic technologies, to create maps of protein interactions. He then makes his maps, which he describes as assembly instructions for molecular networks, available to the broader research community. His ultimate goal, he says, is to translate this basic knowledge into novel diagnostic and therapeutic tools for cancer, cardiovascular disease, and Alzheimer’s disease and other neurodegenerative disorders.

Emili’s vision for the CNSB, he says, is “to create a highly collaborative, multidisciplinary research hub that tackles important fundamental questions in the field by forging new links with interested researchers across both BU campuses, the greater Boston area, and the world.”

The departments of biochemistry and biology will host a reception today on the Medical Campus—open to students and faculty from both campuses—to mark the opening of the center and Emili’s appointment as director, at the Silvio O. Conte Medical Research Center, 71 E. Concord St., from 3 to 5 p.m.

Emili is widely regarded as a leader in proteomics, mass spectrometry, and network systems biology, says David Harris, a MED professor and chair of biochemistry. He says Emili’s work with mass spectrometry will complement that of Catherine E. Costello, a William Fairfield Warren Distinguished Professor, a MED professor of biochemistry, and director of the Center for Biomedical Mass Spectrometry. With Emili’s arrival, Harris says, “we have an incredibly strong presence in multiple kinds of mass spectrometry.”

While the CNSB, as well as Emili’s lab, will be housed within the biochemistry department, he will serve as a bridge between the Medical and Charles River Campuses and will also have an office in the Life Sciences and Engineering Building—and eventually some lab space—at 24 Cummington Mall and teach classes in the biology department.

“He will collaborate widely across the University,” says Harris. “This recruitment from the start was a joint effort of the medical school and the Charles River Campus.”

“It’s really great to have him come in and be a leader,” says Kim McCall, a CAS professor and chair of biology, noting that her department has recently hired three junior faculty in systems biology. “His research is highly collaborative. He’s already talking to people in chemistry. He’s done work related to evolution, so that bridges with our scientists who are doing evolutionary biology. He’ll be important to bioinformatics on the CRC as well.”

Emili’s first map of human protein interactions

A map of human protein interactions, from a 2012 Cell study, a collaboration between Emili and Edward Marcotte of the University of Texas, Austin. The spheres, or dots, are proteins; the lines are interactions between proteins. Emili explains: “The network layout reflects local clustering of proteins to form specific macromolecules—stable complexes—while the broader connectivity between these assemblies shows crosstalk underlying biological circuits and cellular processes. Many of the complexes identified in the study were previously unknown and/or have links to human disease, providing valuable insights into pathobiological mechanisms.” Image courtesy of Emili

“A Google or Facebook of biology”

“If you really want to understand the cell,” Emili says, “you have to understand what the protein molecules do—how they interact, what their functions are, how they’re regulated. The DNA is the code or the raw information, but the proteins are the molecules that are the building blocks. They’re not just abstract information. You can think of them as the construction workers in the cell.”

He thinks of his team of researchers, he says, “as a Google or Facebook of biology,” mapping social networks of proteins that provide clues to how proteins function. “Proteins interact functionally and physically in very dynamic and intriguing ways,” he says. “It’s about who knows who and who’s connected to whom.

“In a disease state, these networks are often perturbed or modified or they fail in some way,” he says, “and if we want to reverse a disease or prevent it, we have to understand how the networks go awry and what something looks like when it’s broken and what it looks like when it’s not broken.”

In 2015, Emili and Edward Marcotte, a University of Texas, Austin, professor of molecular biosciences, led a landmark Nature study that revealed tens of thousands of new protein interactions across nine animal species—baker’s yeast, amoebas, sea anemones, flies, worms, sea urchins, frogs, mice, and humans. Using mass spectrometry to analyze cell samples from each species, the researchers found which proteins worked together in networks and compared their structures across species. Their map provided clues to how these protein associations evolved over time.

“Andrew’s work is highly relevant to a broad range of questions in both basic and applied biomedical research,” says Michael Sorenson, a CAS professor of biology. As an evolutionary biologist, Sorenson says, he particularly appreciates Emili’s 2015 Naturestudy and how it “beautifully illustrates the way in which animal diversity has evolved by building upon and tweaking a common set of fundamental cellular processes that has functioned in much the same way for a billion years or more.”

Emili came to BU from the University of Toronto, where he was a professor of molecular genetics and the Council of Ontario Universities Ontario Research Chair in Biomarker Discovery. He was also a principal investigator and a founding member of the Donnelly Centre for Cellular and Biomolecular Research. He earned a PhD in molecular and medical genetics from the University of Toronto in 1997 and pursued postdoctoral studies as a Damon Runyon/Walter Winchell Cancer Research Fellow with cell geneticist Leland Hartwell, a Nobel laureate, at the Fred Hutchinson Cancer Research Center in Seattle, where Hartwell is president and director emeritus. During that same period, Emili learned protein mass spectrometry with John Yates III, then a University of Washington School of Medicine associate professor of molecular biotechnology, now a Scripps Research Institute professor of chemical physiology.

“BU has tremendous resources,” says Emili, “and given the widespread community support, I think the center can leapfrog ahead and chart out some exciting new terrain to claim and explore.

“Let’s see what riches this inititiative will yield.”

The School of Medicine biochemistry department and College of Arts & Sciences biology department will host a reception, open to students and faculty from both the Charles River Campus and the Medical Campus, to mark the opening of the Center for Network Systems Biology and Andrew Emili’s appointment as director, today, Tuesday, October 3, from 3 to 5 p.m., at the Silvio O. Conte Medical Research Center, 71 E. Concord St., on the Medical Campus.

GIV is Druggable

September 11th, 2017in Departmental News, Research News

Earlier this year, the Garcia-Marcos laboratory reported detailed structural information describing how trimeric G proteins are activated by GBA motifs, protein segments capable of triggering G-protein signaling by a GPCR-independent mechanism. The work focused on GIV, a nucleotide exchange factor for Gαi3. Because we had previously shown that the GIV-Gαi3 interaction is required for cancer metastasis, we investigated if it could be disrupted by small molecules. The identification of such compounds would represent the first step in the development of novel anti-metastatic drugs, an urgently needed arm of current cancer therapeutic strategies.

Disrupting protein-protein interactions (PPIs) like the one established by GIV and Gαi3, however, is notoriously challenging. A significant hurdle to therapeutic development is demonstrating that a given PPI can be targeted by small molecules in the first place – i.e. they tend not to be “druggable.” To establish the druggability of our target, we combined computational approaches and wet laboratory techniques, drawing on insights gathered from our recent studies. We concluded disruption of the PPI target could indeed be achieved by small molecules and furthermore that the mode of action can be readily predicted by utilizing structural information.NF023 Pose FullProtein

 The work establishes a robust pipeline for the discovery and validation of inhibitors of the GIV-Gαi3 interface and identifies a small molecule that can serve in such a role. A limitation is that the small molecule we validated was not suitable for experimentation in cancer cells or patients. The study nonetheless provides an important proof of principle for the druggability of our target, success with which could be achieved by screening larger libraries of chemical compounds. Such high-throughput screens are currently underway in our laboratory.

 This work involved collaboration with the group of Francisco J. Blanco, from the CIC-BioGUNE in Spain and was published in the journal Scientific Reports.

 Reference

The Gαi-GIV binding interface is a druggable protein-protein interaction. DiGiacomo V, de Opakua AI, Papakonstantinou MP, Nguyen LT, Merino N, Blanco-Canosa JB, Blanco FJ, Garcia-Marcos M. Sci Rep. 2017 Aug 17;7(1):8575. doi: 10.1038/s41598-017-08829-7. PMID: 28819150