EMBO Reports

Picker, Louis J

doi: 10.15252/embr.201439052pmid: 24980866

Pariente, Nonia

doi: 10.15252/embr.201439088pmid: 24986905

Pouliot, Chantal; Godbout, Julie

doi: 10.15252/embr.201438590pmid: 24993560

Lyons, Joseph A; Parker, Joanne L; Solcan, Nicolae; Brinth, Alette; Li, Dianfan; Shah, Syed TA; Caffrey, Martin; Newstead, Simon

doi: 10.15252/embr.201338403pmid: 24916388

An enigma in the field of peptide transport is the structural basis for ligand promiscuity, as exemplified by PepT1, the mammalian plasma membrane peptide transporter. Here, we present crystal structures of di‐ and tripeptide‐bound complexes of a bacterial homologue of PepT1, which reveal at least two mechanisms for peptide recognition that operate within a single, centrally located binding site. The dipeptide was orientated laterally in the binding site, whereas the tripeptide revealed an alternative vertical binding mode. The co‐crystal structures combined with functional studies reveal that biochemically distinct peptide‐binding sites likely operate within the POT/PTR family of proton‐coupled symporters and suggest that transport promiscuity has arisen in part through the ability of the binding site to accommodate peptides in multiple orientations for transport.

Abada, Adi; Elazar, Zvulun

doi: 10.15252/embr.201439076pmid: 25027988

Autophagy is the main cellular catabolic process responsible for degrading organelles and large protein aggregates. It is initiated by the formation of a unique membrane structure, the phagophore, which engulfs part of the cytoplasm and forms a double‐membrane vesicle termed the autophagosome. Fusion of the outer autophagosomal membrane with the lysosome and degradation of the inner membrane contents complete the process. The extent of autophagy must be tightly regulated to avoid destruction of proteins and organelles essential for cell survival. Autophagic activity is thus regulated by external and internal cues, which initiate the formation of well‐defined autophagy‐related protein complexes that mediate autophagosome formation and selective cargo recruitment into these organelles. Autophagosome formation and the signaling pathways that regulate it have recently attracted substantial attention. In this review, we analyze the different signaling pathways that regulate autophagy and discuss recent progress in our understanding of autophagosome biogenesis.

Garg, Mansi; Gurung, Resham L; Mansoubi, Sahar; Ahmed, Jubed O; Davé, Anoushka; Watts, Felicity Z; Bianchi, Alessandro

doi: 10.15252/embr.201438919pmid: 24925530

Elongation of the telomeric overhang by telomerase is counteracted by synthesis of the complementary strand by the CST complex, CTC1(Cdc13)/Stn1/Ten1. Interaction of budding yeast Stn1 with overhang‐binding Cdc13 is increased by Cdc13 SUMOylation. Human and fission yeast CST instead interact with overhang‐binding TPP1/POT1. We show that the fission yeast TPP1 ortholog, Tpz1, is SUMOylated. Tpz1 SUMOylation restricts telomere elongation and promotes Stn1/Ten1 telomere association, and a SUMO‐Tpz1 fusion protein has increased affinity for Stn1. Our data suggest that SUMO inhibits telomerase through stimulation of Stn1/Ten1 action by Tpz1, highlighting the evolutionary conservation of the regulation of CST function by SUMOylation.

Fossat, Nicolas; Tourle, Karin; Radziewic, Tania; Barratt, Kristen; Liebhold, Doreen; Studdert, Joshua B; Power, Melinda; Jones, Vanessa; Loebel, David A F; Tam, Patrick P L

doi: 10.15252/embr.201438450pmid: 24916387

Brown, Paige

doi: 10.15252/embr.201439130pmid: 24968892

Jacobs, Howy

doi: 10.15252/embr.201439203pmid: 25085996

Tsai, Li‐Huei; Gräff, Johannes

doi: 10.15252/embr.201438913pmid: 25027989

How to attenuate traumatic memories has long been the focus of intensive research efforts, as traumatic memories are extremely persistent and heavily impinge on the quality of life. Despite the fact that traumatic memories are often not readily amenable to immediate intervention, surprisingly few studies have investigated treatment options for remote traumata in animal models. The few that have unanimously concluded that exposure therapy‐based approaches, the most successful behavioral intervention for the attenuation of recent forms of traumata in humans, fail to effectively reduce remote fear memories. Here, we provide an overview of these animal studies with an emphasis on why remote traumatic memories might be refractory to behavioral interventions: A lack of neuroplasticity in brain areas relevant for learning and memory emerges as a common denominator of such resilience. We then outline the findings of a recent study in mice showing that by combining exposure therapy‐like approaches with small molecule inhibitors of histone deacetylases (HDACis), even remote memories can be persistently attenuated. This pharmacological intervention reinstated neuroplasticity to levels comparable to those found upon successful attenuation of recent memories. Thus, HDACis—or any other agent capable of heightening neuroplasticity—in conjunction with exposure therapy‐based treatments might constitute a promising approach to overcome remote traumata.