Biochemistry

General Trends in the Calnexin-Dependent Expression and Pharmacological Rescue of Clinical CFTR Variants

1. Austin Tedman
2. John A Olson
3. Minsoo Kim
4. Catherine Foye
5. JaNise J Jackson
6. Eli F McDonald
7. Andrew G McKee
8. Karen Noguera
9. Charles P Kuntz
10. Jens Meiler
11. Kathryn Oliver
12. Lars Plate
13. Jonathan P Schlebach

• Curated by eLife

  eLife Assessment

  This important study systematically investigates the effects of calnexin, an endoplasmic reticulum chaperone, on the drug response of approximately 230 disease-causing variants of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Through deep mutational scanning, interactome profiling, and functional assays, the findings provide convincing evidence that calnexin significantly influences both CFTR expression and the efficacy of corrector drugs in a variant-specific manner. These insights advance our understanding of how cellular quality control machinery shapes the pharmacological responsiveness of CFTR variants, which are broadly relevant for researchers in protein folding and genetic disease therapeutics.

Reviewed by eLife

A miniaturized, high-throughput buffer-centric method for protein solubility screening

1. Adrian Svoboda
2. Marina Molineris
3. Tomáš Pluskal
4. Teo Hebra

Reviewed by Arcadia Science

Allosteric modulation of dimeric GPR3 by ligands in the dimerization interface

1. Zeming Qiu
2. Wei Wang
3. Yingying Nie
4. Junxiang Lin
5. Beimeng Zhang
6. Haonan Xing
7. Sanduo Zheng

• Curated by eLife

  eLife Assessment

  Qiu et al. present multiple dimeric structures of GPR3, which reveal the binding mode of the inverse agonist AF64394. The findings provide important insights into the regulation of GPCR3 and potentially other related orphan GPCRs. The authors present convincing evidence of their claims through thoughtful analysis of their cryo-EM structures, mutagenesis, and cell-based assays. This work will be of interest to GPCR investigators, especially those studying the signaling of orphan receptors.

Reviewed by eLife

Inherited CDA-I disease: anemia-associated mutations disrupt CDIN1-Codanin1 complex

1. Martin Stojaspal
2. Tomáš Brom
3. Ivona Nečasová
4. Tomáš Janovič
5. Pavel Veverka
6. Naina Verma
7. Lukáš Uhrík
8. Lenka Hernychova
9. Ctirad Hofr

Reviewed by Review Commons

Amyloid-β fibrils accumulated in preeclamptic placentas suppress syncytialization of cytotrophoblasts

1. Kaho Nishioka
2. Midori Ikezaki
3. Naoyuki Iwahashi
4. Miyu Arakawa
5. Momo Fukushima
6. Noa Mori
7. Mika Mizoguchi
8. Yuko Horiuchi-Tanizaki
9. Megumi Fujino
10. Takami Tomiyama
11. Yoshito Ihara
12. Kenji Uchimura
13. Kazuhiko Ino
14. Kazuchika Nishitsuji

Reviewed by Review Commons

A high-resolution analysis of arrestin2 interactions responsible for CCR5 endocytosis

1. Ivana Petrovic
2. Samit Desai
3. Polina Isaikina
4. Layara Akemi Abiko
5. Anne Spang
6. Stephan Grzesiek

• Curated by eLife

  eLife Assessment

  The authors investigate arrestin2-mediated CCR5 endocytosis in the context of clathrin and AP2 contributions. Using an extensive set of NMR experiments, and supported by microscopy and other biophysical assays, the authors provide convincing data on the roles of AP2 and clathrin in CCR5 endocytosis. This important work will appeal to an audience beyond those studying chemokine receptors, including those studying GPCR regulation and trafficking. The distinct role of AP2 and not clathrin will be of particular interest to those studying GPCR internalization mechanisms.

Reviewed by eLife

Occupancy of the HbYX hydrophobic pocket is sufficient to induce gate opening in the archaeal 20S proteasomes

1. Janelle JY Chuah
2. Madalena R Daugherty
3. David M Smith

• Curated by eLife

  eLife Assessment

  This valuable manuscript describes cryo-EM structures of archaeal proteasomes that reveal insights into how occupancy of binding pockets on the 20S proteasome regulates proteasome gating. The evidence supporting these claims is convincing, although the extrapolation of these findings to the more complex eukaryotic proteasome may prove challenging. This work will be of high interest to researchers interested in proteasome structure and regulation.

Reviewed by eLife

Rac1 Selectively Binds a Specific Lamellipodin Isoform via a Noncanonical Helical Interface

1. Tong Gao
2. Pingfeng Zhang
3. Alison M. Kurimchak
4. James S. Duncan
5. Jinhua Wu

Reviewed by Arcadia Science

Erythrocytosis-inducing PHD2 mutations implicate biological role for N-terminal prolyl-hydroxylation in HIF1α oxygen-dependent degradation domain

1. Cassandra C Taber
2. Wenguang He
3. Geneviève MC Gasmi-Seabrook
4. Mia Hubert
5. Fraser G Ferens
6. Mitsuhiko Ikura
7. Jeffery E Lee
8. Michael Ohh

• Curated by eLife

  eLife Assessment

  In this valuable study, Taber et al used a battery of biophysical and structural approaches to characterize the impact of erythrocytosis-related mutations in prolyl hydroxylase domain protein 2 (PHD2). The authors show that PHD2 mutant proteins are destabilized, thus supporting the tenet that dysregulation of PHD2/hypoxia induced factor (HIF) axis underpins erythrocytosis, while providing incomplete evidence that N-terminal ODD prolyl hydroxylation of HIF is indispensable for these phenotypes. Notwithstanding that this study was found to be of broad interest for a variety of fields focusing on oxygen sensing in homeostasis and pathological states, resolving inconsistencies in the biophysical analysis (e.g., NMR, SEC, and BLI/MST) was thought to be warranted to further corroborate the proposed model.

Reviewed by eLife

Engineering NIR-Sighted Bacteria

1. Stefanie SM Meier
2. Michael Hörzing
3. Cornelia Böhm
4. Emma LR Düthorn
5. Heikki Takala
6. René Uebe
7. Andreas Möglich

• Curated by eLife

  eLife Assessment

  This study establishes bathy phytochromes, a unique class of bacterial photoreceptors that respond to near-infrared light (NIR), as important tools for bacterial optogenetics. NIR light is a key control signal in optogenetics due to its deep tissue penetration and the ability to combine with existing red- and blue-light sensitive systems, but thus far, NIR-activated proteins have been poorly characterized. The strength of the evidence is solid overall, with comprehensive in vitro characterization, modular design strategies, and validation across different hosts. There are some questions that remain – such as the rationale for linker choices, characterization of growth and performance relative to controls, and the physiological significance of color blind effects at alkaline pH – but overall, this study should advance the fields of optogenetics and photobiology and inspire future work.

Reviewed by eLife