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Shao Lab identifies a mechanism that corrects membrane protein localization - Oct 28, 2020

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Eukaryotic cells contain different membrane-bound organelles whose identities and essential functions rely on protein composition. In a study published in Science, the Shao lab and the lab of former HMS Cell Biology student Eunyong Park (now at Berkeley) showed that the P5A-ATPase ATP13A1 (yeast Spf1) dislocates mis-inserted protein transmembrane segments from the endoplasmic reticulum (ER) to maintain organelle homeostasis. Functional work led by postdoctoral fellow Mike McKenna, together with CRSP student Jerry Wei and Alban Ordureau (Harper lab), identified that the P5A-ATPase directly interacts with and removes mislocalized mitochondrial proteins from the ER. Cryo-EM structures of the P5A-ATPase in different conformations determined by the Park lab revealed the molecular basis of substrate selection and dislocation. This work establishes a new class of substrates for this large family of transporters and identifies a previously unknown protein safeguarding mechanism at the ER. 

The Chouchani Lab, led by BBS student Anita Reddy and post-doc Luiz Bozi, describe a pH-sensing metabolite signal that regulates the muscle response to exercise. - Sep 22, 2020

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Using small molecule mass spectrometry approaches the Chouchani Lab team show that during exercise, mouse and human muscle selectively release the mitochondrial metabolite succinate into extracellular fluids. This release is unusual since succinate is a dicarboxylate, which should remain trapped in the cell. But during muscle cell acidification that occurs upon exercise, succinate becomes protonated and transformed to a monocarboxylate.  This renders succinate a transport substrate for the monocarboxylate transporter MCT1, which facilitates pH-gated release. Once released, succinate co-ordinates paracrine signaling through ligation of its cognate GPCR SUCNR1, which is expressed in a variety of non-myofibrillar cells resident in muscle tissue. This newfound succinate secretion pathway is critical for physiological adaptations to exercise in mice, including remodeling of muscle innervation, muscle ECM, and improvements in muscle strength. Based on these findings the Chouchani Lab team propose a general model whereby intracellular energetic status can be communicated systemically through pH-gated succinate release, which could be broadly relevant in other physiological contexts of cellular acidosis. Read more here!

Danial Lab identifies a connection between mitochondrial pyruvate metabolism and inflammation - Jun 24, 2020

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Chronic inflammation is linked to diverse diseases. While the immune cell component of inflammation has been well-studied, cell-intrinsic mechanisms that determine the response of target cells to inflammation are incompletely understood. In recent studies published in Nature Metabolism, the Danial lab identified a connection between mitochondrial pyruvate handling and arginine metabolism through the urea cycle as a cell-intrinsic anti-inflammatory mechanism. They found that pyruvate entry into the TCA cycle via pyruvate carboxylase (PC) leads to increased aspartate synthesis, which supports the aspartate-argininosuccinate shunt to fuel ureagenesis from arginine. This in turndiminishes arginine use for generation of nitric oxide (NO), a chief mediator of inflammatory cytotoxicity. The studies also showed that PC-directed ureagenesis can be regulated by glucose and tested the relevance of this metabolic mechanism in pancreatic beta-cells undergoing inflammation stress in diabetes. The ureagenic effect of PC sheds new insights into metabolic biology of this enzyme and may have implications for diseases where alterations in PC are observed, including diabetes, cancer and inborn errors of metabolism.  

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!

 

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