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News - 12/11/2014 - 9:52pm

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Proteins that are translocated into the endoplasmic reticulum (ER) undergo quality control so that only correctly folded proteins are moved on in the secretory pathway. If a protein cannot reach its native folded state, it is ultimately transported back into the cytosol, poly-ubiquitinated, and degraded by the proteasome, a process called ER-associated protein degradation (ERAD). How proteins are retro-translocated across the ER membrane and moved into the cytosol is only poorly understood. Previous work demonstrated that the ubiquitin ligase Hrd1p is the only membrane component needed for a basic ERAD process. Now, the Rapoport group shows that key steps of basic ERAD can be recapitulated with purified components (Stein et al., Cell 158, 1375-1388). Hrd1p binds misfolded protein substrates, discriminating them from folded proteins. Subsequently, both Hrd1p and substrate are poly-ubiquitinated. Next, the Cdc48p ATPase complex binds and uses the energy of ATP hydrolysis to release substrate from Hrd1p. Finally, ubiquitin chains are trimmed by the de-ubiquitinating enzyme Otu1p, which is recruited and activated by the Cdc48p complex. The Cdc48-dependent extraction of poly-ubiquitinated proteins from the membrane can be reproduced with reconstituted proteoliposomes. These results provide a major step forward towards the goal to recapitulate ERAD with purified components and to elucidate the molecular mechanism of the process.

News - 12/11/2014 - 9:45pm

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The endoplasmic reticulum (ER) is an important membrane-bound organelle in all eukaryotic cells. Depending on cell type and functional state, the ER membrane can adopt different morphologies, including a network of interconnected tubules, and sheets that can contain fenestrations or be stacked on top of each other.  How these different morphologies are generated is unclear. A collaboration of different groups, including the Rapoport group, resulted in a recent paper that presents a comprehensive theoretical model, which explains the formation and interconversion of virtually all known ER morphologies (Shemesh et al., 2014, Proc. Natl. Acad. Sci. USA PMID:25404289). The model is based on two types of membrane-shaping proteins (R- and S-type proteins), exemplified by the reticulons and lunapark, which both stabilize the high membrane curvature in cross-sections of tubules and sheet edges, but favor straight or concave sheet edges, respectively. Dependent on the concentrations of R- and S-type proteins, membrane morphologies can be generated that consist of tubules, sheets, sheet fenestrations, and sheet stacks with helicoidal connections. In a tubular ER network, lunapark stabilizes three-way junctions, i.e. small triangular sheets with concave edges. The model agrees with experimental observations and explains how curvature-stabilizing proteins determine ER morphology.

News - 12/02/2014 - 8:29pm


Cell celebrated its 40th anniversary by revisiting "landmark" Cell publications, an esteemed list that includes six papers from five faculty members: Dan Finley, Wade Harper, Yang Shi, Bruce Spiegelman, and Junying Yuan.  One of these papers, Yang Shi's research identifying the first histone demethylase, LSD1, was also honored and showcased as an "Annotated Classic."

News - 11/24/2014 - 5:50pm

Dr. Randy King

Randy King, the Harry C. McKenzie Professor of Cell Biology at Harvard Medical School, has been awarded the American Association of Medical Colleges Excellence in Teaching award for his involvement and innovation in the laboratory, in the classroom and across the curriculum at HMS.  

Randy has played a critical role in the major curriculum redesign of the four-year MD program at HMS.  He is leading the design and implementation of an interdisciplinary first-year introductory course called “Foundations,” which integrates fundamentals of cell biology, biochemistry, pharmacology, anatomy, genetics, immunology, pathology and microbiology.  To learn more, click here.

News - 11/17/2014 - 10:27pm

Dr. Junying Yuan

The Elizabeth D. Hay Professorship in Cell Biology honors the legacy of Betty Hay, a pioneering figure at Harvard Medical School and in the field of cell biology.  We are pleased to announce that Dean Jeffrey Flier has named Dr. Junying Yuan, Professor of Cell Biology, as the inaugural recipient of this endowed chair.

Dr. Hay was the first woman to be appointed as a full professor in a preclinical department at the Medical School in 1969, and served as the Chair of the Department of Anatomy (later the Department of Cell Biology) for sixteen years.  Through her expertise in electron microscopy, Dr. Hay was the first to show that the extracellular matrix plays a vital role in determining cell behaviors, including cell shape, cell-to-cell signaling, wound repair, cell adhesion, and tissue function. Her work provided some of the first evidence for the existence of ECM receptors (now known as integrins) on the epithelial surface, and her discoveries formed the foundations for an entirely new field of cellular biology.  She was also responsible for showing that cell differentiation is not an irreversible process, and the first to describe the transition of epithelial cells into mesenchymal cells, a process central to development and cancer metastasis.  

Junying Yuan joined the Department of Cell Biology as an Assistant Professor in 1996 and was appointed full professor in 2000.  As a graduate student, Dr. Yuan studied the relatively unknown field of cell death, and her work would eventually help lead Bob Horvitz to a Nobel Prize in 2002.  Her research provided the first evidence of the existence of a targeted cellular death mechanism--apoptosis--that counterbalances cell proliferation, which transformed the cell death field from a descriptive science into a molecular discipline.  More recently, Dr. Yuan discovered a regulated form of necrosis, called necroptosis, and has spent the last few years studying its molecular mechanism and identifying small molecule inhibitors, some of which have generated significant interest as possible therapeutics.  

Congratulations again to Dr. Yuan!

News - 11/13/2014 - 2:48pm

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Cytoskeletal molecular motors move uni-directionally along their tracks. This poses multiple problems: How do they get to the start of the track? Once there, how do they stay there to capture cargo? A candidate for retaining the microtubule-based motor dynein at the start of its track (microtubule plus ends) is a ubiquitous regulator called Lis1. The Reck-Peterson Lab, in collaboration with the lab of Andres Leschziner (Harvard) has been seeking to answer the second question. Previously they showed that Lis1, a gene mutated in the rare neurodevelopmental disease lissencephaly, had the functional properties necessary to stall dynein on microtubules: when bound to Lis1, dynein keeps going through the ATP hydrolysis cycle that normally powers the motor yet, rather than walking, it remains tightly bound to its track. This led to the proposal that Lis1 was working as a “clutch”, uncoupling dynein’s engine (the ATP hydrolysis cycle) from its wheels (the cycle of microtubule binding and release). In the latest issue of eLife, the Reck-Peterson and Leschziner groups now shed light on the molecular mechanism of Lis1’s affect on dynein. They reported three distinct 3D cryo-electron microscopy structures of the dynein/Lis1 complex, representing the first 3D structures of dynein bound to any of its regulators. Their structures revealed that Lis1 binding to dynein causes a repositioning of dynein’s main mechanical element, the “linker”. Based on these structures they hypothesized that Lis1 physically blocks an interaction between dynein’s linker and AAA+ motor ring, known to be required for dynein to release from microtubules. Förster resonance energy transfer (FRET), single-molecule and in vivo assays supported this hypothesis. Strikingly, shortening dynein’s linker to a point where it could physically bypass Lis1 made dynein Lis1-insensitive, showing that Lis1 keeps dynein in a persistent microtubule-bound state by directly blocking progression of its mechanochemical cycle.

For more details, click here.

News - 10/02/2014 - 8:50am

The Bjorkman-Strominger-Wiley Prize was established this year by Harvard University's Department of Molecular & Cellular Biology to encourage inter-lab cooperation, in honor of Pamela Bjorkman and Jack Strominger and the late Don Wiley. While all three were working at Harvard in the 1980s, they collaborated on research into the MHC protein’s crystal structure and antigen presentation. The first winners of this award are Samara Reck-Peterson and Andres Leschziner for their labs’ work on the motor protein dynein. According to MCB Chair Alex Schier, “the two labs combined their expertise in structural biology, biophysics, biochemistry and cell biology to be much more than the sum of their parts.”

News - 10/02/2014 - 8:46am

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PINK1 and PARKIN – two proteins mutated in early onset Parkinson’s Disease - are known to function in a signaling cascade that leads to ubiquitylation of mitochondrial outer membrane proteins on damaged mitochondria, but the precise mechanism through by which PINK1 activates PARKIN ubiquitin ligase activity and retention on the mitochondrial membrane is poorly understood. In the most recent issue of Molecular Cell, Alban Ordureau in the Harper Lab used quantitative proteomics and a technique called ubiquitin AQUA to examine the kinetics and specificity of PINK1 and PARKIN-dependent ubiquitin chain synthesis on damaged mitochondria in vivo. Through mechanistic and biochemical analysis, as well as live-cell imaging, the authors define multiple steps in the process, revealing a feed-forward mechanism for PARKIN activation and retention on mitochondria. PINK1 phosphorylation of S65 in the UBL of PARKIN leads to activation of its ubiquitin ligase activity by 2400-fold, which in turn promotes the initial synthesis of K6, K11, K48, and K63 ubiquitin chains on mitochondria by PARKIN. Ubiquitin units within newly synthesized ubiquitin chains are then phosphorylated by PINK1 on S65, the residue homologous to S65 in the UBL of PARKIN. This, in turn, serves as a binding site (Kd = 17 nM) for activated PARKIN, leading to retention of PARKIN on poly-ubiquitinated mitochondria, which could support both further ubiquitin chain synthesis and recruitment of proteins to promote mitophagy.  Our data reveal a feed-forward mechanism that explains how PINK1 phosphorylation of both PARKIN and poly-UB chains synthesized by PARKIN drives a program of PARKIN recruitment and mitochondrial ubiquitylation in response to mitochondrial damage. This work also provides a framework for quantitative analysis of phosphorylation and ubiquitin dependent signaling systems in vitro and in vivo.

News - 09/02/2014 - 10:27am

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Phosphorylation of proteins on tyrosine is particularly important in the control of cell proliferation and differentiation, and drives many of the changes seen in cancer cells. Protein tyrosine phosphorylation has previously been thought to occur only inside cells, where it can control changes in cell structure, movement, and gene expression. In a recent article in Cell, the Whitman Lab found a new kind of tyrosine kinase, VLK, that is secreted into the extracellular environment. VLK phosphorylates a broad range of extracellular proteins, including key regulators of tumor invasion and metastasis, blood clotting, and inflammation, pointing to a new mechanism for the control of protein function outside of cells.

News - 08/22/2014 - 9:56am

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Hummingbirds are avid nectar drinkers, and their ability to perceive sugars enabled their extensive radiation in a new ecological niche. In a recent article in Science, Maude Baldwin, a visiting scientist in the Liberles Lab, uncovered a noncanonical mechanism for sweet taste detection that evolved in hummingbirds since divergence from swifts, their insect-eating relatives. Phylogenetic analysis indicates that an ancestor of birds- likely within Dinosauria- lost an essential subunit of the only known vertebrate sweet receptor, raising questions of how specialized nectar-feeders sense sugars. Receptor expression studies revealed that the ancestral umami receptor (T1R1-T1R3 heterodimer) was repurposed in hummingbirds to function as a carbohydrate receptor. Furthermore, the molecular recognition properties of T1R1-T1R3 guided taste behavior in captive and wild hummingbirds. These studies illustrate how changing the ligand recognition properties of a single sensory receptor can facilitate the evolution of new species. 

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