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Liao lab reveals how chemotherapy drugs induce a conformational switch in the multidrug transporter ABCG2 - May 11, 2020

Liao Lab
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Resistance to chemotherapy is a complication frequently encountered during treatment of difficult recurring cancers. The ability of cancerous cells to resist the cytotoxic effects of chemotherapeutics is often mediated by ABC transporters such as P-glycoprotein, ABCG2, and MRP1, which function to actively pump anti-cancer drugs out of cells. Among these transporters the structure of ABCG2 is unique, with inverted topology and a lack of domain swapping between transmembrane helices. The mechanisms by which ABCG2 recognizes and transports diverse chemotherapy compounds has remained elusive. 

In a recent paper published in Nature Communication, the Liao Lab determined a series of cryo-EM structures of ABCG2 bound to different chemotherapy compounds. These structures along with accompanying biochemical assays reveal how anti-cancer drugs induce a conformational switch of the transporter, and how different compounds elicit distinct effects on transporter conformation and function. These results have important implications for future drug development.

How a Small Molecule Paradoxically Activates the Complex it Inhibits - May 07, 2020

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Most drugs are small molecules that cause a therapeutic effect by binding to a target protein. Some small molecules inhibit a protein’s function, whereas others work by activating the protein. In work published in Nature Chemical Biology, the King Lab reports the surprising identification of a small molecule that can do either, depending on cellular regulatory context. 

The King lab has pioneered the development of small molecule inhibitors of the Anaphase-Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that is required for anaphase and mitotic exit. In work led by graduate student Katie Richeson, the paper reports the surprising finding that the APC/C inhibitor apcin can paradoxically stimulate APC/C activity under conditions when the APC/C is antagonized the spindle checkpoint, a signaling pathway that normally restrains APC/C activity during mitosis. These findings indicate that apcin causes net inhibition of APC/C when spindle checkpoint activity is low, or net activation of APC/C when spindle checkpoint activity is high, indicating that apcin can act as either an inhibitor or an activator of APC/C depending on physiological context.  

Dr. Dan Finley elected to the Academy of Arts and Sciences, class of 2020 - Apr 30, 2020

Dan Finley

Dr. Dan Finley was just elected to the Academy of Arts and Sciences, class of 2020!  The mission of the Academy is to champion scholarship, civil dialogue, and useful knowledge.  It is one of the country’s oldest learned societies and independent policy research centers, and it convenes leaders from the academic, business, and government sectors to respond to the challenges facing the nation and the world.  Some fellow class members include Anne Hochschild (Chair of Microbiology at HMS), author Ann Patchett, musician Joan Baez, and filmmaker Richard Linklater.  Congrats to Dan!


Rapoport Lab unveils the mechanism of ER-associated protein degradation mediated by Hrd1 complex - Apr 27, 2020

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ER-associated protein degradation (ERAD) disposes of misfolded endoplasmic reticulum (ER) proteins. ERAD also mediates the regulated degradation of folded ER proteins and is hijacked by certain viruses. Misfolded luminal ER proteins undergo ERAD-L: they are retrotranslocated into the cytosol, polyubiquitinated, and degraded by the proteasome. ERAD-L is mediated by the Hrd1 complex, a complex of five proteins, but the mechanism of retrotranslocation has remained mysterious. In new findings published in Science, the Rapoport Lab, with the help of the lab of Maofu Liao, used cryo-electron microscopy to determine the architecture of the entire active Hrd1 complex. These structures, along with crosslinking and molecular dynamics simulation results, suggest how the Hrd1 complex recruits and retrotranslocates its substrates. The study shows that the Hrd1 complex retrotranslocates misfolded luminal ER proteins through two “half-channels” juxtaposed in a thinned membrane. This arrangement lowers the energy barrier for a polypeptide loop to pass through the membrane. The demonstrated novel mechanism may also be found in other translocation systems.

Protein structure from experimental evolution - Dec 17, 2019

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The Sander lab has demonstrated that artificial evolution can provide sufficient information to correctly compute protein 3D structure. Proteins, which are made up of a sequence of amino acids, are fundamental units of biological function and evolution. The key to protein function lies in how these amino acids interact with one another to produce intricate protein 3D structure. In a recent paper published in the journal Cell Systems, the researchers mimicked natural evolution in a laboratory setting by generating hundreds of millions of protein variants and selecting the hundreds of thousands of sequences that retain function. Statistical inference of amino acid interactions from these experimentally evolved sequences enabled them to compute protein structures strikingly similar to those determined by X-ray crystallography. This technology opens the door to a new experimental method for the determination of protein structures - complementary to X-ray crystallography, NMR and cryoEM - and may contribute to a better understanding of the complexities of natural evolution and lead to practical applications in synthetic biology.

Hemsley and Lunadel Matthews retire after a combined 61 years of service - Nov 19, 2019

After a combined 61 years of service, Hemsley and Lunadel Matthews are retiring from our department. This power couple has worked tirelessley over the last 30 years to ensure that albs are fully stocked to function on a daily basis. They have worked in our department longer than most of us can remember, and they will be sorely missed. We thank them for their service and wish them the best on their next chapter! Learn about their future plans here.

Farese/Walther Lab sheds light on a "drop's props" - Nov 18, 2019

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Lipid droplets (LDs) store lipids for making cellular membranes and for metabolic energy, but it’s unclear exactly how they’re made. A team led by Robert Farese, Tobias Walther, and Jeeyun Chung (HMS/HSPH) discovered that a complex of lipid droplet assembly factor 1 in interaction with seipin, an endoplasmic reticulum (ER) protein, is the core protein machinery that drives the formation of LDs and determines where they form in the ER. Appearing in Developmental Cell, the work could have implications for common metabolic diseases and industrial applications, such as production or biofuels. 

Dr. Susan Shao awarded prestigious 2019 Packard Foundation Fellowship - Oct 19, 2019

Dr. Susan Shao

Assistant Professor Dr. Sichen (Susan) Shao was announced as one of 22 early-career scientists and engineers in the 2019 class of Packard Fellows for Science and Engineering from the David and Lucile Packard Foundation. This $875,000 award will help the Shao Lab study the molecular mechanisms that detect and handle problems at different steps of protein biosynthesis by biochemically rebuilding cellular pathways for mechanistic and structural dissection. Recipients of this prestigious award have gone on to receive numerous accolades, including Nobel Prizes, MacArthur Fellowships, and election to the Nation Academies.

Haigis Lab determines activated T cells need alanine - Sep 27, 2019

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In order to properly respond to invading pathogens, T cells transition from a state of quiescence to a state of activation. This transition is metabolically challenging and to support their growth and functional demands, T cells rely on environmental nutrients. In their recent study published in Cell Reports, the Haigis Lab (in collaboration with the labs of Arlene Sharpe and Josh Rabinowitz) identified extracellular alanine as one of the extracellular nutrients required to support T cell activation. Although alanine is a non-essential amino acid, meaning that it can be synthesized inside the cell via transaminase activity, T cells uniquely rely on the extracellular alanine pool due to low alanine aminotransferase expression. By performing stable isotope tracing, the lab showed that alanine is not catabolized inside the cell but is instead directly shunted into protein synthesis.