Unlocking the bacterial SecY translocon

SummaryThe Sec translocon performs protein secretion and membrane protein insertion at the plasma membrane of bacteria and archaea (SecYEG/β), and the endoplasmic reticular membrane of eukaryotes (Sec61). Despite numerous structures of the complex, the mechanism underlying translocation of pre-proteins, driven by the ATPase SecA in bacteria, remains unresolved. Here we present a series of biochemical and computational analyses exploring the consequences of signal sequence binding to SecYEG. The data demonstrate that a signal sequence-induced movement of transmembrane helix 7 unlocks the translocon and that this conformational change is communicated to the cytoplasmic faces of SecY and SecE, involved in SecA binding. Our findings progress the current understanding of the dynamic action of the translocon during the translocation initiation process. The results suggest that the converging effects of the signal sequence and SecA at the cytoplasmic face of SecYEG are decisive for the intercalation and translocation of pre-protein through the SecY channel

Gene-Environment Interaction in a Conditional NMDAR-Knockout Model of Schizophrenia

Interactions between genetic and environmental risk factors take center stage in the pathology of schizophrenia. We assessed if the stressor of reduced environmental enrichment applied in adulthood provokes deficits in the positive, negative or cognitive symptom domains of schizophrenia in a mouse line modeling NMDA-receptor (NMDAR) hypofunction in forebrain inhibitory interneurons (Grin1ΔPpp1r2). We find that Grin1ΔPpp1r2 mice, when group-housed in highly enriched cages, appear largely normal across a wide range of schizophrenia-related behavioral tests. However, they display various short-term memory deficits when exposed to minimal enrichment. This demonstrates that the interaction between risk genes causing NMDA-receptor hypofunction and environmental risk factors may negatively impact cognition later in life

A carbapenem antibiotic inhibiting a mammalian serine protease: structure of the acylaminoacyl peptidase–meropenem complex

The structure of porcine AAP (pAAP) in a covalently bound complex with meropenem was determined by cryo-EM to 2.1 � A resolution, showing the mammalian serine-protease inhibited by a carbapenem antibiotic. AAP is a modulator of the ubiquitin-proteasome degradation system and the site of a drug–drug interaction between the widely used antipsychotic, valproate and carbapenems. The active form of pAAP – a toroidal tetramer – binds four meropenem molecules covalently linked to the catalytic Ser587 of the serine- protease triad, in an acyl–enzyme state. AAP is hindered from fully processing the antibiotic by the displacement and protonation of His707 of the catalytic triad. We show that AAP is made susceptible to the association by its unusually sheltered active pockets and flexible catalytic triads, while the carbapenems possess sufficiently small substituents on their b-lactam rings to fit into the shallow substrate-specificity pocket of the enzyme