Jefferson University | Biochemistry & Molecular Biology | In the Loop Newsletter | Spring 2018

SIDNEY KIMMEL MEDICAL COLLEGE AT THOMAS JEFFERSON UNIVERSITY

IN THE LOOP DEPARTMENT OF BIOCHEMISTRY & MOLECULAR BIOLOGY |

SPRING 2018

New Insights into How Cells Respond to Hormones PAGE 6

From the Chair As I write this it has been nearly a year since I was appointed the 18th Chair of the Department of Biochemistry and Molecular Biology at Jefferson. For the decade prior to this, I had the privilege of observing the Department as an outsider, gaining great admiration for the faculty and for Dr. Jeffrey Benovic who served as Chair during that period. Jeff is a brilliant scientist who helped foster the careers of junior faculty who are now among Jefferson’s most esteemed investigators. His leadership steadied the Department through many, many changes, at the level of Medical College Dean, Cancer Center Director, Provost, and University President. Like Jeff, the other faculty members that comprise the Department represent a truly world-class group of scientists and educators whose reputations contribute significantly to Jefferson’s international stature. Finally, it is not lost on me that the current faculty are only the most recent incarnation of a Department that traces its roots to the 1824 founding of Jefferson Medical College. So, it was with a great sense of reverence and

Thomas Jefferson University Department of Biochemistry and Molecular Biology Steven B. McMahon, PhD Professor and Chair Senior Associate Provost, Programmatic Science Peter Ronner, PhD Professor and Vice Chair for Education Gino Cingolani, PhD Professor and Vice Chair for Research Diane Merry, PhD Professor and Vice Chair for Faculty Development and Engagement Emad Alnemri, PhD Thomas Eakins Professor Teresa Alnemri, PhD Research Assistant Professor Jeffrey Benovic, PhD Thomas Eakins Professor

Steven B. McMahon, PhD

Anshul Bhardwaj, PhD Research Assistant Professor

Professor and Chair Department of Biochemistry and Molecular Biology Sidney Kimmel Medical College

Erik Debler, PhD Assistant Professor

Senior Associate Provost, Programmatic Science Thomas Jefferson University

humility that I accepted this position. Fortunately, working with this group of faculty and our remarkable administrative team has made this year one of the most rewarding of my career.

I can’t think of words suitable for thanking all of them for welcoming me into their family.

My goal with this newsletter, and other vehicles, is to help inform you of some of the outstanding achievements made by our faculty. Too often the true heroes among us go unrecognized and our faculty clearly fall into this group. (Ultimately, I hope to share with you achievements of some of our impressive alumni as well.) Academic Medical Centers like Jefferson are defined by their position at the cutting edge of medical science. The fundamental knowledge unearthed for us by basic scientists like those in the Department of Biochemistry and Molecular Biology is the currency by which these Centers are judged. For nearly two hundred years, this Department has been home to the faculty that provide foundational support for Jefferson’s claim to a place among the top medical centers in the world.

So, what’s next as the Department and the Medical College move toward the dawn of their third century? To be sure, there will be more of the same, meaning groundbreaking discoveries that rewrite textbooks and have a profound impact on patients with diseases like cancer, neurodegeneration, heart disease, inflammation, and asthma, among others. We will also be growing in lots of ways. There will be more new faculty, like Dr. Erik Debler, who you can read about further on in this newsletter. There will be new research space as we complete the renovation of 20,000 square feet of state of the art laboratories in Jeff Alumni Hall. There will be a renewed outward looking face for the Department, one that engages alumni, philanthropists, private foundations and our peers across the nation and around the globe. Finally, there will be a number of other initiatives that we will roll out over the next year. So, please stay In The Loop.

I would love to hear from you with any comments, memories or ideas about the Department.

Miki Fujioka, PhD Research Instructor Howard Gamper, PhD Research Assistant Professor Ya-Ming Hou, PhD Professor James Jaynes, PhD Professor Hideko Kaji, PhD Professor James Keen, PhD Professor Yohei Kirino, PhD Assistant Professor Alexander Mazo, PhD Professor Svetlana Petruk, PhD Research Assistant Professor Anna Pluciennik, PhD Research Instructor Michael Root, MD, PhD Associate Professor Charles Scott, PhD Research Assistant Professor Philip Wedegaertner, PhD Professor Eric Wickstrom, PhD Professor Edward Winter, PhD Professor

The Department of Biochemistry & Molecular Biology FRONT ROW (L TO R): Rosemarie Fleming-Troendle, Dr. Eric Wickstrom, Dr. Miki Fujioka, Dr. Hideko Kaji, Dr. Svetlana Petruk, Dr. Ya-Ming Hou, Dr. Yohei Kirino, Heather Krupinski. 2ND ROW: Lai Siu, Dr. Emad Alnemri, Dr. Jeffrey Benovic, Dr. Diane Merry, Dr. Teresa Alnemri, Lisa Peeler. 3RD ROW: Dr. Philip Wedegaertner, Dr. Alexander Mazo, Dr. Steven McMahon, Dr. James Jaynes, Dr. Edward Winter, Dr. Erik Debler. 4TH ROW: Dr. Charles Scott, Dr. Gino Cingolani, Dr. Anna Pluciennik, Dr. Anshul Bhardwaj, Dr. Michael Root. NOT PICTURED: Dr. Howard Gamper, Dr. James Keen, Eneida Nieves.

Administrative Staff Our Administrative Team is located in Room 350 of the Bluemle Life Sciences Building.

Rosemarie Fleming-Troendle Administrator

Heather Krupinski Administrative Assistant

Eneida Nieves Assistant to the Chair

Lisa Peeler Administrative Coordinator

Lai Siu Financial Analyst

THOMAS JEFFERSON UNIVERSIT Y | DEPARTMENT OF BIOCHEMIS TRY & MOLECUL AR BIOLOGY | 1

New Vice Chairs We are pleased to announce the appointments of Diane Merry, PhD ➀, and Gino Cingolani, PhD ➁, as Vice Chairs in the Department of Biochemistry and Molecular Biology at the Sidney Kimmel Medical College. Dr. Merry will serve as Vice Chair for Faculty Development and Engagement and Dr. Cingolani as Vice Chair for Research.

They join Dr. Peter Ronner, PhD ➂, the long-standing Vice Chair for Education within the Department.

Dr. Merry, who holds the rank of Professor, joined the Department of Biochemistry and Molecular Biology in 1999.

Her research has been consistently funded by grants from the NIH as well as multiple private foundations. Dr. Merry is internationally recognized for her discoveries exploring the role of protein aggregation in neurodegenerative diseases. Dr. Merry is also a member of Jefferson’s Farber Institute for Neuroscience and the Jefferson Committee on Research.

Dr. Cingolani, also a Professor in the Department of Biochemistry and Molecular

Biology at the Sidney Kimmel Medical College, joined the Department in 2009.

Similar to Dr. Merry, Dr. Cingolani’s research has been funded by multiple grants from the NIH and other agencies. Dr. Cingolani is a structural biologist whose discoveries have provided fundamental advances in the areas of nuclear transport and viral protein function. Drs. Merry and Cingolani currently co-Chair the Faculty Recruitment Committee within the Department.

When he announced these new appointments, Dr. McMahon said, “Diane and Gino bring tremendous energy and vision to their roles in the Department. Both they and their colleagues in the Department have been remarkably generous with their time and effort as we have launched a number of new initiatives. As the largest of Jefferson’s Basic Science Departments, the Department of Biochemistry and Molecular Biology has a great deal of heavy lifting that needs to be done. I could not ask for more talented and capable partners in this undertaking than Peter, Diane and Gino.”

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Editorial Appointments Gino Cingolani, PhD, Professor, was selected as one of three new co-editors for Acta Crystallographica D: Structural Biology. Acta D is an important structural biology Journal that plans to expand its audience to chemists, biochemists and biologists not directly involved in developing/using crystallographic methods. As co-editor for Acta D, Dr. Cingolani will oversee the peer-review process of research papers and thematic reviews mainly dealing with biological motors, structural virology and macromolecular trafficking.

Yohei Kirino, PhD, Assistant Professor, joined the Editorial Board of Scientific Reports (Molecular Biology section).

Scientific Reports is an online, open access journal from the publishers of Nature.

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Jefferson.edu/Biochemistry

Recent Awards and Honors

2016-2017 academic year

RESEARCH AWARD

RESEARCH AWARD

Alexander Mazo, PhD, received the Michael and Melina Pellini Award for Innovation in the Biomedical Sciences. This award is given annually to a SKMC faculty member in recognition of exceptional research accomplishments that have “led to new concepts or approaches to experimentation or patient care.” Dr. Mazo’s award broadly recognizes his contributions to the field of epigenetics and is specifically for elucidating mechanisms that connect replication of the genome to gene expression.

Emad Alnemri, PhD, was chosen as a recipient of the Falk Medical Research Trust Catalyst Award. His application was entitled: “Role of DFNA5 in the Anti-Tumor Immune Response.” The Catalyst Research Award Program provides one year of seed funding to support high-risk, high-reward projects that address critical scientific and therapeutic roadblocks within the Program’s principal areas of focus.

The Program is designed to enable planning and development of projects, teams, tools, techniques and management infrastructure necessary to successfully compete for two-year award through the Transformational Research Award Program.

RESEARCH AWARD

RESEARCH AWARD

Yohei Kirino, PhD, received the SKMC Early Career Investigator Award for Distinguished Achievement in Biomedical Research. This award is given annually to a faculty member for outstanding research carried out “in basic and/or clinical/ translational research within the first ten years of his/her initial faculty appointment.” Dr. Kirino’s award is for elucidating molecular mechanisms used by small regulatory RNAs to control cellular processes.

Jeffrey Benovic, PhD, and Philip Wedegaertner, PhD, are part of the Uveal Melanoma Team with Andrew Aplin, PhD, that was awarded the Falk Medical Research Trust Transformational Award. The Transformational Awards Program provides $1,000,000 for a two-year funding cycle to successful Catalyst Awardees to continue their work tackling critical scientific and therapeutic roadblocks and thereby opening avenues for treating and curing disease. The Transformational Award provides a bridge to the technology transfer process for moving an exciting health care innovation to the next step in commercial development.

Transformational Awards are granted based on both scientific merit and having successfully attained the proposed milestones and benchmarks of the Catalyst Award, thus demonstrating its successful execution within the proposed budget and projected timeframe.

more > THOMAS JEFFERSON UNIVERSIT Y | DEPARTMENT OF BIOCHEMIS TRY & MOLECUL AR BIOLOGY | 3

NON-FACULTY AWARD

TEACHING AWARDS

Koree Ahn, PhD, former PhD student, has been selected as one of five recipients of the 2017 Herbert Tabor Young Investigator Awards for his paper “Complex interplay of kinetic factors governs the synergistic properties of HIV-1 entry inhibitors.” The Herbert Tabor Young Investigator Award is given to celebrate young authors who contribute top content to The Journal of Biological Chemistry. This award will be presented at the annual ASMBM meeting in April 2018 and will feature a special Spotlight Session.

James Jaynes, PhD, and Edward Winter, PhD, received the Professor Fredric Rieders Faculty Prize in Graduate Education. This award is given annually in recognition of “outstanding performance by a JCBS faculty member engaged in the education of graduate students.”

TEACHING AWARD

EDITORS’ PICK Michael Root, MD, PhD, and team recently published groundbreaking studies on the inhibition of HIV that were chosen as an “Editors’ Pick” at The Journal of Biological Chemistry. This recognition was given specifically for the publication by Drs. Root and Koree Ahn, a former PhD student from Dr. Root’s lab, titled “Complex interplay of kinetic factors governs the synergistic properties of HIV-1 entry inhibitors.”

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Peter Ronner, PhD, received the SKMC Career Educator Award. This award is given annually in recognition of “outstanding contributions to education in academic medicine both within his/her institution and to education in his/her field over a career.” Dr. Ronner also received the Dean’s Award for Excellence in Education. This award is for faculty who “demonstrate superior effectiveness as a teacher, devote significant time/effort to teaching over a sustained period of time, or for faculty who demonstrate major contributions to an educational course, clerkship or program of training.” Additionally, Dr. Ronner was named AACP Teacher of the Year (2016-2017) from the Jefferson College of Pharmacy.

This Jefferson College of Pharmacy student-nominated, Executive Boardselected award is given to a faculty member based on demonstration of student-centered teaching, innovative course development, and effective teaching strategies.

FACULTY APPOINTMENT

FACULTY HONOR

Gino Cingolani, PhD, Professor and Vice Chair of Biochemistry and Molecular Biology, has been named a permanent member of the National Institutes of Health study section Prokaryotic Cell and Molecular Biology [PCMB]. Michael Root, MD, PhD, has been appointed to a Vice Dean role in the Jefferson College of Biomedical Sciences (JCBS).

Jeffrey Benovic, PhD, was a keynote speaker at both the September 2017 Temple University Annual Research Day and the September 2017 Department of Pharmacology Retreat at Case Western Reserve University. Dr. Benovic was also a plenary speaker at the November 2017 Joint Meeting of Argentine Bioscience Societies.

Jefferson.edu/Biochemistry

Opening up Chromatin for Cell Differentiation Sidney Kimmel Cancer Center | Spring 2017

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wo studies from Alexander Mazo, PhD, provide new insights into the structure of chromatin and its implications for cellular differentiation.

In Molecular Cell, Mazo, from the Department of Biochemistry & Molecular Biology, found that in mammalian embryonic stem cells (ESCs) including human ESCs, modification of histones that help organize DNA into the coiled chromatin structure of chromosomes plays a crucial role in facilitating cell differentiation. This depends on lineage-specific transcription factors that associate with their target genes on DNA. The regulatory regions of all genes that are repressed before the induction of differentiation contain tightly condensed chromatin, which is marked by a repressive histone modification, H3K27me3. This type of chromatin contains the most highly condensed structure of DNA-wrapped nucleosomes in the genome, presenting a challenge for newly induced transcription factors to overcome the barriers to entry into such condensed chromatin. During DNA replication, nascent DNA is transiently free of the repressive histone mark H3K27me3, providing a critical “window of opportunity” for the recruitment of lineage-specific transcription factors to the DNA. In Cell Reports, Mazo’s team focused on multipotent hematopoietic progenitor cells (HPCs) that generate all terminally differentiated blood cells and found that the same chromatin-decondensing mechanism is important for their recruitment of lineagedetermining transcription factors. CD34-postitive HPCs were found to shed the repressive histone mark H3K27me3 just after DNA replication, allowing recruitment of transcription factors that drive cytokine-induced erythroid or myeloid differentiation. More primitive types of HPCs exhibit a very rapid association of nascent DNA with the repressive H3K27me3 histone mark, suggesting that HPCs may utilize special

mechanisms of chromatin modification for recruitment of specific transcription factors during the early stages of their lineage specification. Nevertheless, the similarity between the transient disappearance of the same histone mark from nascent DNA of both pluripotent stem cells (ESCs) and multipotent hematopoietic progenitors (HPCs) raises the possibility that “this decondensation of chromatin occurs irrespective of the induced cell lineage, and thus might constitute a previously unknown general mechanism of induction of differentiation for any cell,” according to Mazo. Since the chromatin decondensing mechanism operates in HPCs, it is likely relevant to gene regulatory changes observed in leukemia cells, which arise when normal hematopoietic cells lose their ability to differentiate properly. Many types of cancer are thought to involve cancer stem cells or other tumor-initiating cells that have lost their ability to differentiate, possibly due to abnormal functioning of this chromatin-based lineage-specification mechanism.

Further research on this mechanism may make it possible to manipulate the process, allowing the programming of ESCs or patient-derived stem cells into desired cell lineages for use in disease therapies.

Bruno Calabretta, MD, PhD

Alexander Mazo, PhD Neal Flomenberg, MD

Svetlana Petruk, PhD Lorraine Iacovitti, PhD

Not Pictured: Dr. Steven B. McMahon THOMAS JEFFERSON UNIVERSIT Y | DEPARTMENT OF BIOCHEMIS TRY & MOLECUL AR BIOLOGY | 5

New Insights into G ProteinReceptor

Dr. Jeffrey L. Benovic

Dr. Konstantin Komolov

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Jefferson.edu/Biochemistry

Coupled Signaling and Regulation A collaborative study by the laboratories of Jeffrey L. Benovic, PhD, in the Department of Biochemistry and Molecular Biology at Thomas Jefferson University and the Sidney Kimmel Cancer Center at Jefferson, and Dr. Brian K. Kobilka in the Department of Molecular and Cellular Physiology at the Stanford University School of Medicine, provides new insights into a general mechanism regulating signaling from G protein-coupled receptors (GPCRs).

Two senior postdoctoral researchers, Dr. Konstantin E. Komolov of the Benovic lab and Dr. Yang Du of the Kobilka lab, share co-first authorship of the new study, which is published in the April 20th issue of Cell.

GPCRs physically span the cell membrane. There they play a central role in enabling cells to respond to extracellular stimuli, including various hormones, neurotransmitters, peptides, and proteins. Stimulation of the GPCR results in activation of cellular G proteins, which in turn modulate the activity of downstream effectors that ultimately control numerous cellular functions, such as cell growth and motility. These signaling events are tightly regulated. One such regulator is a family of proteins called GPCR kinases (GRKs). GRKs bind to and phosphorylate the stimulated receptor, after which a different protein called arrestin then specifically binds to the phosphorylated GPCR. Through this process, GRKs deactivate G protein signaling and activate arrestin-mediated signaling. As Benovic explains, GRKs play a central role in switching cells from G protein signaling to arrestin-mediated signaling, which is critical in maintaining normal cellular homeostasis.

In the Cell study, the Benovic and Kobilka groups study the interaction of a particular GPCR kinase, GRK5, with the ß2-adrenergic receptor (ß2AR), a cell membrane bound GPCR that is activated (stimulated) by binding to catecholamines such as adrenaline. Their findings reveal key mechanistic features of how these two proteins interact, and how this interaction leads to conformational changes in the GRK that are essential for mediating receptor phosphorylation.

In order to study these interactions within the GRK5/ß2AR complex, the researchers first had to replicate the formation of the stable complex, which in cells is associated with the cell membrane. They found that acidic lipids, like the naturally occurring ones found in cell membranes, greatly enhanced the binding of GRK5 to ß2AR. They further found that although GRK5 would bind to an inactive form of ß2AR, it was binding of GRK5 to an activated (agonist-bound)

THOMAS JEFFERSON UNIVERSIT Y | DEPARTMENT OF BIOCHEMIS TRY & MOLECUL AR BIOLOGY | 7

ß2AR that produced a functional complex, one in which GRK5 could phosphorylate ß2AR. This suggested that agonist binding created conformational changes in ß2AR structure, making it the preferred GRK5 binding partner and enabling formation of a functional GRK5/ß2AR complex.

With an active, functional complex in hand, the team used a comprehensive integrated approach to analyze the molecular interactions of GRK5 with ß2AR. They demonstrated that GRK5 binding to ß2AR involved interactions at multiple sites to produce a functional complex. In addition, just as the binding of an agonist caused changes in ß2AR structure and shape, the binding of ß2AR was shown to induce conformational changes in GRK5 – by disrupting key internal contacts between two major GRK5 domains, causing them to separate which in turn caused the kinase domain of GRK5 to adopt an active conformation.

Finally, using multiple cross-linking Mass Spectroscopy (MS) strategies, the Jefferson and Stanford researchers mapped the GRK5/ß2AR interface, identifying the protein regions that directly participated in the interactions. Those data guided computational modeling and docking studies, permitting the investigators to generate a 3-D model of the GRK5/ß2AR complex – one that shows a possible progression of the conformational changes associated with three potential stages of complex formation. Data from additional studies, using hydrogendeuterium exchange MS, supported the team’s model of the active GRK5/ß2AR complex. “The molecular model derived from these studies provides important insights into a common mechanism of GRK-GPCR interaction, raising the exciting possibility of exploiting this mechanism to control GPCR signaling,” adds Benovic.

The new findings hold promise for many clinical applications in the future. GPCRs are the target of ~30% of drugs currently on the market, including drugs for the treatment of cancer, cardiovascular and airway disease, as well as various neurological and metabolic disorders. Because GRKs play a central role in regulating GPCR function, a better understanding of the mechanisms involved in this process provides an

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The molecular model derived from these studies provides important insights into a common mechanism of GRK-GPCR interaction, raising the exciting possibility of exploiting this mechanism to control GPCR signaling.

opportunity to manipulate this pathway in treating various diseases.

Another illustration of the importance of understanding the physiological roles of GRK-GPCR interactions in human physiology comes from the report, by another group, that a naturally occurring difference in a single amino acid of the GRK5 protein may enhance phosphorylation of ß2AR. Especially intriguing, it has been proposed that this amino acid difference may confer some protection against the development of congestive heart failure for the large percentage of the African American population that have this amino acid difference.

Future plans include dissecting further the interaction of GRK5 with ß2AR using high-resolution structural imaging approaches such as X-ray crystallography and cryo-electron microscopy, and also analyzing the dynamics of the interaction using approaches such as radiolytic footprinting and double electron electron resonance (DEER) spectroscopy. Studies are also envisioned to explore the broader significance of the newly reported results by examining other interacting pairs of GPCRs and GRKs. Commenting on the long-term goals of this project, Benovic notes that “understanding the structure of a GRK-GPCR complex should help us develop small molecules that enable us to either enhance or inhibit GRK regulation of the receptor, which should have tremendous implications for treating a wide variety of diseases.”

This work was supported by NIH awards R01GM068857 and P01HL114471 (to J.L.B.) and R01GM083118 (to B.K.K.), the Mathers Foundation (to B.K.K.) a Stanford University Terman Faculty Fellowship (to R.O.D.) and the National Research Foundation of Korea funded by the Korean government (NFR- 2015R1A1A1A05027473 and NRF- 2012R1A5A2A28671860) (to K.Y.C.).

Article Reference: Konstantin E. Komolov, Yang Du, Nguyen Minh Duc, Robin M. Betz, João P. G. L. M. Rodrigues, Ryan D. Leib, Dhabaleswar Patra, Georgios Skiniotis, Christopher M. Adams, Ron O. Dror, Ka Young Chung, Brian K. Kobilka, and Jeffrey L. Benovic, “Structural and Functional Analysis of a ß2-Adrenergic Receptor complex with GRK5,” 2017, Cell 169, 407-421.

DOI: 10. 1016/j.cell.2017/

Jefferson.edu/Biochemistry

XXV Biennial Conference on Phage/Virus Assembly Recognizing Dr. Gino Cingolani’s success in organizing the 2017 PVA Conference

For more information on the XXV Biennial Conference on Phage/Virus Assembly, please visit www.xxv-pva.net.

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e recognize the outstanding efforts of Dr. Gino Cingolani, Professor and Vice Chair, Department of Biochemistry and Molecular Biology, in organizing the XXV Biennial Conference on Phage/Virus Assembly. Dr. Cingolani was nominated for this prestigious appointment and co-hosted this scientific global event in late August, 2017, with Dr. Venigalla Rao of The Catholic University of America, Washington, DC. By volunteering to host this international conference, Dr. Cingolani provides a wonderful opportunity for scientists around the world to become acquainted with Thomas Jefferson University and its groundbreaking research. The PVA Conference on Phage/ Virus Assembly is a continuation of a series that was initiated in 1968. At first it was a meeting of scientists working on mechanisms of bacteriophage assembly, it expanded to include animal and plant viruses. The conference alternates with the FASEB Virus Assembly meeting. At present, the Conference is highly interdisciplinary, bringing together virologists, geneticists, biochemists, biophysicists, and structural biologists working on various aspects of virus assembly and virus infection, including medically relevant viruses and archaeal viruses.

THOMAS JEFFERSON UNIVERSIT Y | DEPARTMENT OF BIOCHEMIS TRY & MOLECUL AR BIOLOGY | 9

Welcome to New BMP Students

BENJAMIN BARNHART Eastern University INTEREST:

QINGQING CAO Baylor University INTEREST:

Inflammation; Signaling

“The biggest surprise for me after arriving at Jefferson was the friendly working environment. Professors, classmates and staff are all nice and very willing to help, especially as a non-English speaker. Both my parents are professors in China; my father specializes in toxicology, while my mother is a civil engineer. My father has always encouraged me to study science, as he too enjoys science.

Outside of the lab, I enjoy playing the piano and singing Italian Opera.”

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Enzymology

“I really enjoy the relationship between chemical structure and chemical function. In BMP, you get to see biological mechanisms at their most specific levels. Every functional group, even every atom, is important for the processes we study. The meticulousness and artful quality that biochemistry has excites me! Equally exciting are the results from my study of sex-hormones and their relation to tRNA cleavage.

Seems like every experiment raises new questions for us. My parents were always enthusiastic about school and science in general. I often talk to them about the classes I’m taking and about working in a lab to study different aspects of living cells. I explain to them what I can about tRNA, as my research is centered around that topic. My dad was a high-school chemistry teacher early in his career. During my free time, I enjoy playing soccer with my roommates, eating in Chinatown, and attending exercise classes at Jefferson’s gymnasium.”

Jefferson.edu/Biochemistry

GRACE MCCARTHY Washington and Jefferson University INTEREST:

NICHOLAS SWANSON St. Joseph’s University INTEREST:

Neurodegeneration

“The greatest success of my scientific career thus far occurred during my rotation in Dr. Gino Cingolani’s lab.

Using electron microscopy, I was able to visualize a complex of a mysterious class of ejection proteins found in bacterial viruses! From this, we are gaining insight into how bacterial viruses eject their viral genome across host cell envelopes. Exciting research with medical relevance! When I’m not in the lab, I spend my time volunteering with No One Dies Alone (NODA) here at Jefferson Hospital, a group that provides companionship to patients on comfort care during their passing who would otherwise be alone. Every situation is unique and provides a deep introspective experience that molds my understanding of life in ways that science cannot.”

Nuclear Receptors; Cancer

“Whether trying to figure out my direction of studies, or if I have a specific lab question, someone is always very willing to help—professors and HANNAH SCHAPIRO upperclassmen alike. In the Brody lab, Skidmore College I worked on developing a screen for INTEREST: Protein Structure and HuR inhibitors for pancreatic cancer

Function; RNA treatment. I am very interested in cancer research and want to develop new cancer treatments. When this “My favorite non-science course in assay began to work, I became excited college was History of Fashion and thinking of all the possible treatments Clothing. Outside of lab, I love to cook!” that could be discovered using this assay. When I’m not in the lab, I love to play tennis. I’ve been playing since I was 12 years old and also played in college.

It’s a great way for me to destress!”

THOMAS JEFFERSON UNIVERSIT Y | DEPARTMENT OF BIOCHEMIS TRY & MOLECUL AR BIOLOGY | 11

FACULTY PROFILE

Welcome Erik Debler, PhD

Assistant Professor, Department of Biochemistry and Molecular Biology

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r. Erik Debler received his PhD training in Biophysics with Ian Wilson at The Scripps Research Institute in La Jolla, CA, where he worked on the structure of the IL-2 receptor signaling complex and catalytic antibodies, publishing 12 papers in journals such as Science and PNAS. Erik’s postdoctoral training was with Nobel Laureate Günter Blobel at Rockefeller University, where he published 12 papers on the structure of the nuclear pore complex and on proteins involved in chromatin biology of parasitic organisms, including the human parasite Trypanosoma brucei. He discovered bromodomains as novel targets for anti-parasitic treatment. Dr. Debler’s research group

focuses on the structure-function relationships of macromolecular assemblies involved in the differentiation and regulation of protozoan parasites of medical importance. Major research themes are elucidating the role of chromatinassociated proteins in the life cycle control of Trypanosoma brucei and targeting these processes to develop novel drugs against parasitic infectious diseases.

Günter Blobel states “It’s been a great pleasure to have Erik in my laboratory. He is one of the most outstanding and productive young biologists I have encountered in my career.

After his numerous contributions towards the atomic structure determination of the Nuclear Pore Complex (NPC), which is the largest and most versatile transport channel in eukaryotic

evolution, he has independently and successfully established his own line of research in molecular and structural parasitology. This work beautifully merges his expertise in structural biology with infectious disease biology to further our understanding of host pathogen interactions and shows great promise for development of innovative therapies for a range of protozoan diseases including malaria, trypanosomiasis, and leishmaniasis. Erik has all the essential qualities to efficiently and successfully run his own lab and become a leader in his field.”

Dr. Debler’s office and research laboratory are located on the 8th floor of the Bluemle Life Sciences Building. He can be reached at Erik.Debler@jefferson.edu.

Dr. Debler’s research group focuses on the structure-function relationships of macromolecular assemblies involved in the differentiation and regulation of protozoan parasites of medical importance.

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Jefferson.edu/Biochemistry

FACULTY PROFILE

40 Years of Innovation:

Hideko Kaji, PhD

In 1968 when Marshal Nirenberg was awarded the Nobel Prize for defining “the genetic code and its function in protein synthesis” (along with Holley and Khorana), he graciously acknowledged in his Nobel lecture that his eureka moment came only because he stood on the shoulders of giants in his field. Among those whose critical discoveries he named were Avery, Beadle, Tatum, Watson, Crick, Sanger, Benzer, Brennan, Berg and Leder. On equal footing, he described how the “important findings” of Hideko and Akira Kaji on the association of tRNA and ribosomes, provided the “clue to the solution” of how base composition within codons specifies each amino acid. Dr. Kaji’s discoveries that were already a part of history when Nirenberg highlighted them half a century ago were only the beginning of an inspirational career that is still going strong here at Jefferson.

Congratulations on your anniversary, Hideko!

Grant Awards Adding to the Department’s extramural funding portfolio in 2017, faculty were awarded new grants from both the private and federal sector.

Jeffrey Benovic NIH – R01

Characterization of beta-arrestin-biased beta 2-adrenergic receptor signaling in cardiovascular function

Jeffrey Benovic

NIH – R35 MIRA

Regulation of G protein-coupled receptor signaling and trafficking

Gino Cingolani

NIH – R01

Multisubunit Viral ATPases that couple ATPhydrolysis to genome translocation

Gino Cingolani

NIH – R01

Regulation of nuclear import through importin alpha isoforms

Ya-Ming Hou

J. Hopkins Packard Running RAN translation in C9orf72 tractable models Center for ALS

Alex Mazo

NIH – Multi PI R01 The role of the decondensed structure of nascent chromatin during T cell differentiation

Alex Mazo

NIH – Multi PI R01 Structure of post-replicative chromatin during cell reprogramming in fibrotic disease

Anna Pluciennik

NIH – R03

Role of USP7 in pathogenicity of spinal and bulbar muscular atrophy

Anna Pluciennik

KDA

Targeting AR toxicity in SBMA by modulation of USP7 activity

Michael Root

NIH – R01

Mechanisms of HIV-1 membrane fusion

Philip Wedegaertner AHA

Mechanisms of localization and trafficking of GRK5 and GRK6

NIH (National Institutes of Health) KDA (Kennedy’s Disease Association) AHA (American Heart Association) THOM A S JEFFERSON UNIVERSIT Y | DEPARTMENT OF BIOCHEMIS TRY & MOLECUL AR BIOLOGY | 13

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Introducing the inaugural edition of the Department of Biochemistry & Molecular Biology newsletter!

To support the research and education missions of the Department of Biochemistry and Molecular Biology, please visit Giving.Jefferson.edu.

What Every Healthcare Professional Should Know: A General Medical Update ON THE COVER:

A model for GRK5 interaction with the ß₂-adrenergic receptor (ß₂AR).

Structural constraints derived from mass spectrometry analysis of the cross-linked ß₂AR-GRK5 complex were applied to the crystal structure of the he Four Seasons, Jackson Hole Registration Fee: ß₂AR in complex with Gs and the Medical at Images ofwebsite Dr. Netter Usedfee inincludes New Biochemistry Book pend a week with Jefferson faculty the annual alumniClassic Beginning $595 (see for details) elongated conformation of at GRK5 • All education sessions and CME credit inter CMEdetermined symposium. experts from several

by Renowned molecular dynamics • Welcome Superbowl reception (Feb. 1)of Biochemistry and Molecular Biology, pecialties simulations will present.of ionic lock disrupted Dr. Peter Ronner, Professor in the SKMC Department • Breakfast and afternoon snacks (Feb. 2-5) Essential Biochemistry (Elsevier). recently published the first edition of the textbook Netter’s sangivamycin-bound GRK5.

The eaturing: Jefferson President Stephen Klasko, MD, MBA, • One dinneroriginal ticket illustrations (Feb. 4)* from the artist and physician, Frank L. Netter, MD. The textbook includes docking model was refined and nd Provost Mark Tykocinski, MD, Anthony F. and Gertrude • Access additional areaJefferson discounts In addition to Dr.to Ronner, Thomas University contributors include Drs. David validated by hydrogen deuterium . DePalma Dean, Sidney Kimmel Medical College at Thomas Axelrod, Samir Ballas, Jeffrey Benovic, Bruno Calabretta, Gino Cingolani, Masumi Eto, Andrzej exchange-mass spectrometry studies. efferson University See the full schedule of presenters and topics at: Fertala, Elizabeth Gilje, Christopher Haines, Steven Herrine, Jan Hoek, Ya-Ming Hou, Serge (See page 6) Jefferson.edu/jeffcme/AlumniCME pdates and Clinical Pearls in: Jabbour, Erica Johnson, Leo Katz, Diane Merry, Michael Natter, Charles Scott, Edward Winter, Register Online Now! Cardiac and Vascular Disease • Treatment of Hepatitis andCPhilip Wedegaertner.

February 1-5, 2015

Geriatric Medicine Complementary and

• and more!

Questions? Contact the SKMC Office of CME at 1-888-JEFF-CME or jeffersoncme@jefferson.edu