Molecular Biology

Structural basis for the folding of PINK1 by the HSP90–CDC37 chaperone complex

1. Kei Okatsu
2. Hayato Yamamoto
3. Akinori Okamoto
4. Shinya H Goto
5. Yumiko Nishimoto
6. Yukihiko Sugita
7. Takeshi Noda
8. Shuya Fukai

• Curated by eLife

  eLife Assessment

  This study presents a high-quality cryo-EM structure of the human kinase PINK1 in complex with the HSP90-CDC37 chaperone complex, capturing a partially folded intermediate in which the C-lobe and C-terminal extension are structured while the N-lobe remains unfolded and engaged by the HSP90 clamp. The structural data are broadly consistent with a recently published structure of the same complex, providing useful insight into early steps of PINK1 maturation and highlighting residues linked to familial Parkinson's disease. However, the mechanistic conclusions remain incomplete because the manuscript does not experimentally validate key hypotheses raised by the structure, including the functional roles of the C-lobe interface, the HPNI motif, the C-terminal extension, or the proposed competition between HSP90 and TOM20.

Reviewed by eLife

Distinct Mechanisms for Inhibition of SARS-CoV-2 Main Protease: Dimerization Promoted by Peptidomimetic Inhibitors and Disrupted by Ebselen

1. Chengxi Liu
2. Qinyu Jia
3. Chang Zhao
4. Zhong-Ping Yao

• Curated by eLife

  eLife Assessment

  This important study provides a comprehensive comparison of the mechanisms through which different inhibitors affect the SARS-CoV-2 main protease, a pivotal antiviral drug target, and suggests a potentially broad-spectrum strategy to inhibit this critical viral enzyme by disrupting its dimerization states. However, whereas the biophysical analyses of the dimer stability are convincing, evidence supporting this new mode of mechanism to inhibit the main protease is incomplete and would benefit from a correlation of the biophysical observations with functional activity. With the functional validation part strengthened, this work would be of interest to biochemists and virologists working on anti-coronavirus drug discovery.

Reviewed by eLife

FRG1 Regulates Nonsense-Mediated mRNA Decay by Modulating UPF1 Levels

1. Ananya Palo
2. Talina Mohapatra
3. Anamika Singh
4. Shithij Thalakkat
5. Suryasikha Mohanty
6. Rajeeb Kumar Swain
7. Manjusha Dixit

• Curated by eLife

  eLife Assessment

  This useful study by Palo et al proposes that FRG1 functions as a negative regulator of Nonsense-Mediated mRNA decay (NMD) by associating with the exon junction complex (EJC) and destabilizing UPF1 independently of DUX4. The authors present solid evidence to dissect the relationship between FRG1 and DUX4 in NMD. However, the evidence to support the claim that FRG1 is a component of the EJC or the NMD machinery is incomplete.

Reviewed by eLife

Specialization of ubiquitin ligases to distinct nucleic acid sensors

1. Ibrahim Syed
2. Sheng Chen
3. David J. Peeler
4. Paul F. McKay
5. Marco A. Briones-Orta
6. Jennifer A. Bohn
7. Robin J. Shattock
8. Daniel Gonçalves-Carneiro

Reviewed by Review Commons

A novel high-throughput single-cell DNA sequencing method reveals hidden genomic heterogeneity in the unicellular eukaryote Leishmania

1. Gabriel H Negreira
2. Pieter Monsieurs
3. Jean-Claude Dujardin
4. Malgorzata A Domagalska

• Curated by eLife

  eLife Assessment

  This important study, which tackles the challenge of analyzing genome integrity and instability in unicellular pathogens by introducing a novel single-cell genomics approach, presents compelling evidence that this new tool outperforms standard whole-genome amplification techniques. While thorough and rigorous, the work's impact would increase by providing scripts and data, as well as a description of the biological relevance that would make this method more appealing to the broad community studying genetic heterogeneity in diverse organisms.

Reviewed by eLife

HP1β and H3K9me3 Regulate Olfactory Receptor Choice and Transcriptional Identity

1. Martín Escamilla-del-Arenal
2. Rachel Duffié
3. Hani Shayya
4. Valentina Loconte
5. Axel Ekman
6. Lena Annika Street
7. Adan Horta
8. Daniele Canzio
9. Kevin Monahan
10. Carolyn Larabell
11. Marko Jovanovic
12. Stavros Lomvardas

Reviewed by PREreview