News

Home / News

News - 04/27/2016 - 6:05pm

Yang Shi elected to the American Academy of Arts and Sciences, 2016 Class
Yang Shi

We congratulate faculty member Yang Shi, one of four members of the Harvard Medical School community who are part of this year’s class of national and international leaders elected to the American Academy of Arts and Sciences.

Founded in 1780, AAAS is one of the country’s oldest and most prestigious honorary societies and independent policy research centers, convenes leaders from the academic, business and government sectors to respond to the challenges facing the nation and the world.

To see the other members of the 2016 class, click here.

News - 03/23/2016 - 2:29pm

Rapoport lab determines structure of the active translocon
[Click to enlarge]

A recent paper by Li et al. (Rapoport lab, with help from Hidde Ploegh’s lab at the MIT), reports a crystal structure of the active protein translocation channel, which had been a “holy grail” in the field. Previously, the Rapoport lab had reported crystal structures of the idle channel (van den Berg, B. et al. Nature 427, 36-44 (2004)) and of a complex of the channel with the translocation ATPase SecA (Zimmer et al. Nature 455, 936-943 (2008)). Structures of the idle channel show that the largest subunit, SecY, consists of two halves that form an hourglass-shaped pore and a lateral gate that faces lipid. The constriction in the middle of the membrane is formed from six pore ring residues. The cytoplasmic funnel is empty, while the extracellular funnel is filled with a plug domain. When SecA binds to the channel, it inserts a two-helix finger into the cytoplasmic opening of the channel and partially opens the lateral gate. The new structure now contains the SecY channel, SecA, and a short segment of a secretory protein fused into the two-helix finger of SecA. This segment inserts into the channel as a loop, displacing the plug domain. The hydrophobic core of the signal sequence forms a helix that sits in a groove outside the lateral gate, while the following polypeptide segment intercalates into the gate. The C-terminal section of the polypeptide loop is located in the channel, surrounded by four pore ring residues. The structure shows that the hydrophobic regions of signal sequences exit the lateral gate and partition into the lipid phase, explaining their diversity in sequence and length. A comparison with other structures shows that this mechanism of signal sequence recognition is universal, regardless of the organism and mode of translocation, and also applies to bilayer-spanning domains of nascent membrane proteins.

News - 02/24/2016 - 10:44pm

Rapoport Lab clarifies mechanism of a bacterial O-glycosyltransferase
[Click to enlarge]

Many proteins are glycosylated on Ser or Thr residues, but the mechanism of O-glycosylation is only poorly understood. A recent study by Chen et al. (Rapoport Lab, in collaboration with Paul Sullam’s lab at San Francisco Veteran Affairs Medical Center) reports on the mechanism by which the cytosolic O-glycosyltransferase GtfA/B of Streptococcus gordonii modifies the Ser/Thr-rich repeats of adhesin, a protein that mediates the attachment of the bacterium to host cells. Crystal structures and biochemical experiments indicate that, during a first phase of glycosylation, the conformation of GtfB is restrained by GtfA to bind substrate with unmodified Ser/Thr residues. In a slow second phase, GtfB recognizes residues that are already modified with N-acetylglucosamine by converting into a relaxed conformation. These results explain how the glycosyltransferase modifies a progressively changing substrate molecule.

News - 02/24/2016 - 5:24pm

Liao Lab determines high-resolution cryo-EM structures of synaptic RAG1-RAG2 complex to reveal the molecular mechanism of V(D)J recombination
[Click to enlarge]

Diverse repertoires of antigen-receptor genes that result from combinatorial splicing of V(D)J gene segments are hallmarks of vertebrate immunity. The (RAG1-RAG2)2 recombinase precisely recognizes and cleaves two different recombination signal sequences (12-RSS and 23-RSS), and forms synaptic complexes only with one 12-RSS and one 23-RSS, a dogma known as the 12/23 rule that governs the recombination fidelity. As described in a recent paper in Cell, the Liao Lab (in collaboration with Dr. Hao Wu's lab at Boston Children's Hospital) used single-particle cryo-electron microscopy (cryo-EM) to determine the structures of synaptic RAG1-RAG2 complexes at up to 3.4 Å resolution. These structures reveal an RSS-induced closed conformation that activates catalysis and uncovers the molecular basis for the 12/23 rule.

News - 02/24/2016 - 9:22am

Spiegelman Lab identifies Slit2-C as secreted protein that regulates adipose tissue thermogenesis
[Click to enlarge]

This new work, by Katrin Svensson in the Spiegelman Lab and recently published in Cell Metabolism, has found a new function for Slit2, a protein secreted from beige cells. Slit2-C, a C-terminal cleaved fragment of Slit2 circulates in plasma and improves glucose homeostasis in mice by activating a thermogenic gene expression program and the classical PKA signaling pathway in fat cells. These findings establish a previously unknown peripheral role for a Slit2 fragment that has therapeutic potential for the treatment of diabetes and other metabolic disorders.

News - 02/22/2016 - 11:19am

Näär Lab identifies compound that prevents multidrug-resistant fungi from pumping out drugs
Anders Näär

An international team led by researchers at Harvard Medical School and Massachusetts General Hospital has devised a new way to approach the problem of multidrug-resistant fungal infections that can be life-threatening to people with weakened immune systems. The Näär Lab and Gerhard Wagner's lab identified this compound from a library of 150,000 small molecules. To learn more, see here.

News - 12/09/2015 - 3:57pm

Anders Näär receives Research to Prevent Blindness Stein Innovation Award
Anders Näär

RPB Stein Innovation Awards provide funds to researchers in the ophthalmology department and to basic science or other relevant vision researchers outside of the ophthalmology department (but within the institution) with a common goal of understanding the visual system and the diseases that compromise its function. These awards are intended to provide seed money to proposed high-risk/high-gain vision science research which is innovative, cutting-edge, and demonstrates out-of-the-box thinking.


Congrats to Anders!

News - 10/29/2015 - 10:29am

New pathway of energy expenditure from the Spiegelman Lab
[Click to enlarge]

The epidemic of obesity and diabetes have increased interest in pathways that cause an increase in metabolic rates. The classical pathway of adaptive thermogenesis involves the function of mitochondrial Uncoupling Protein 1 (UCP1) in brown fat. This new work by the Spiegelman lab and published recently in Cell, shows that beige fat cells have another pathway used to generate heat and dissipate chemical energy. Their mitochondria utilize a futile cycle of creatine phosphorylation/dephosphorylation to elevate respiration and expend calories as heat. This new pathway may offer new insights into thermal regulation and offer new targets for human metabolic disorders.

News - 10/07/2015 - 4:59pm

Harper Lab elucidates the molecular underpinnings of delivery of ferritin to autophagosomes through the NCOA4 pathway and demonstrates a role for NCOA4 in erythroid development
[Click to enlarge]

NCOA4 is a selective cargo receptor for the autophagic turnover of ferritin, a process critical for regulation of intracellular iron bioavailability. However, how ferritinophagy flux is controlled and the roles of NCOA4 in iron-dependent processes are poorly understood. Through analysis of the NCOA4-FTH1 interaction, the Harper lab demonstrated that direct association via a key surface arginine in FTH1 and a C-terminal element in NCOA4 is required for delivery of ferritin to the lysosome via autophagosomes. Moreover, NCOA4 abundance is under dual control via autophagy and the ubiquitin proteasome system. Ubiquitin-dependent NCOA4 turnover is promoted by excess iron and involves an iron-dependent interaction between NCOA4 and the HERC2 ubiquitin ligase. In zebrafish and cultured cells, NCOA4 plays an essential role in erythroid differentiation. This work reveals the molecular nature of the NCOA4-ferritin complex and explains how intracellular iron levels modulate NCOA4-mediated ferritinophagy in cells and in an iron-dependent physiological setting.

Mancias, JD, Pontano Vaites L, Nissim S, Biancur DE, Kim AJ, Wang X, Liu Y, Goessling W, Kimmelman AC, Harper JW. (2015) Ferritinophagy via NCOA4 is required for erythroid development and is regulated by an iron dependent HERC2-mediated proteolysis. eLife

News - 10/07/2015 - 4:55pm

Through a systematic proteomic analysis of the VCP–UBXD adaptor network, the Harper Lab identifies a role for UBXN10 in regulating ciliogenesis
[Click to enlarge]

The AAA-ATPase VCP (also known as p97 or CDC48) uses ATP hydrolysis to ‘segregate’ ubiquitylated proteins from their binding partners, and has been implicated in numerous pathways ranging from ERAD to repair of damaged DNA. VCP acts through UBX-domain-containing adaptors that provide target specificity, but the targets and functions of UBXD proteins remain poorly understood. Through systematic proteomic analysis of UBXD proteins in human cells reported in Nature Cell Biology, the Harper lab revealed a network of over 195 interacting proteins, implicating VCP in diverse cellular pathways based on Gene Ontology analysis. Through detailed analysis of the interaction partners for the unstudied adaptor UBXN10, they uncover a role for this adaptor and VCP/p97 in ciliogenesis.  UBXN10 associates with the intraflagellar transport B (IFT-B) complex, which regulates anterograde transport into cilia. Using TIRF microscopy in living cells, the demonstrate that UBXN10 is localized in cilia and traffics in cilia with the IFT-B complex. Moreover, deletion of UBXN10 using gene-editing renders cells unable to form cilia. Pharmacological inhibition of VCP destabilized they IFT-B complex and increased trafficking rates. Depletion of UBXN10 in zebrafish embryos causes defects in left–right asymmetry, which depends on functional cilia. This study provides a resource for exploring the landscape of UBXD proteins in biology and identifies an unexpected requirement for VCP–UBXN10 in ciliogenesis.

Raman, M, Sergeev, M, Garnaas M, Lydeard JR, Huttlin EL, Goessling W, Shah JV, and Harper JW. (2015) Systematic proteomics of the VCP–UBXD adaptor network identifies a role for UBXN10 in regulating ciliogenesis. Nature Cell Biology

Pages