Structural Basis for Receptor-Mediated Selective Autophagy of Aminopeptidase I Aggregates

SummarySelective autophagy mediates the degradation of various cargoes, including protein aggregates and organelles, thereby contributing to cellular homeostasis. Cargo receptors ensure selectivity by tethering specific cargo to lipidated Atg8 at the isolation membrane. However, little is known about the structural requirements underlying receptor-mediated cargo recognition. Here, we report structural, biochemical, and cell biological analysis of the major selective cargo protein in budding yeast, aminopeptidase I (Ape1), and its complex with the receptor Atg19. The Ape1 propeptide has a trimeric coiled-coil structure, which tethers dodecameric Ape1 bodies together to form large aggregates. Atg19 disassembles the propeptide trimer and forms a 2:1 heterotrimer, which not only blankets the Ape1 aggregates but also regulates their size. These receptor activities may promote elongation of the isolation membrane along the aggregate surface, enabling sequestration of the cargo with high specificity

Super-assembly of ER-phagy receptor Atg40 induces local ER remodeling at contacts with forming autophagosomal membranes

The ER is subject to autophagy (ER-phagy) for turnover, with Atg40 acting as a receptor to sequester ER with Atg8 in autophagosomes. Here, the authors show that Atg40 is clustered by interaction with Atg8 to generate local membrane curvature and promote autophagosome packing

Cystatin C in risk prediction after transcatheter aortic valve replacement: a retrospective analysis

Abstract Aims No study has evaluated the prognostic value of the chronic kidney disease (CKD) classification by cystatin C‐based estimated glomerular filtration rate (eGFR) (CKDCys classification) in patients undergoing transcatheter aortic valve replacement (TAVR). This study aimed to compare the prognostic value of CKDCys classification and CKD classification by creatinine‐based eGFR (CKDCr classification) in risk prediction after TAVR. Methods and results We retrospectively analysed consecutive 219 patients with symptomatic severe aortic stenosis who underwent TAVR at our institute between December 2016 and June 2019. Pre‐operative CKDCr and CKDCys classifications were evaluated for their prognostic value of 2‐year major adverse cardiovascular and cerebrovascular events (MACCE) after TAVR. MACCE was defined as the composite of all‐cause mortality, non‐fatal myocardial infarction, stroke, and rehospitalization for worsening congestive heart failure. Participants had a median age of 86.0 years and were predominantly female (76.9%). In 96.6% of the cases, TAVR was performed using transfemoral access. The median creatinine‐based eGFR (52.85 mL/min/1.73 m2) was higher than the cystatin C‐based eGFR (41.50 mL/min/1.73 m2). Downward reclassification in CKD stages based on eGFRCys was observed in 49.0% of patients. During a median follow‐up period of 575.5 (interquartile range: 367.0–730.0) days, 58 patients presented with MACCE. CKDCys classification, but not CKDCr classification, significantly stratified the risk of 2‐year MACCE in patients after TAVR by log‐rank test (P = 0.003). In multivariate Cox regression analysis, only CKDCys stage 3b [hazard ratio (HR) = 4.37; 95% confidence interval (CI): 1.28–14.91; P = 0.019] and CKDCys stage 4 + 5 (HR = 3.72; 95% CI: 1.06–12.99; P = 0.040) were significant predictors of MACCE after adjustment for potential confounders. Conclusions The CKDCys classification could better assess the risk than the CKDCr classification in patients undergoing TAVR. CKDCys stage 3b and stage 4 + 5 correlated with adverse outcomes

Crystallization and preliminary X-ray analysis of aspartate transcarbamoylase from the parasitic protist Trypanosoma cruzi

Aspartate transcarbamoylase, the second enzyme of the de novo pyrimidine-biosynthetic pathway, from T. cruzi has been purified and crystallized for X-ray structure analysis