Reviews & Analysis

The multisubunit phospholipid transport system Mla has been under scrutiny to determine whether it functions as an exporter or an importer. Structural studies accompanied by the reconstitution of the entire Mla system into proteoliposomes now reveal that ATP binding and hydrolysis drive phospholipid import.

The protein SARM1 is an executioner of axon degeneration through its NAD⁺ hydrolase activity. Three groups now report structures of human SARM1 in an inactive state and identify NAD⁺ as an allosteric inhibitor, illuminating an elegant mechanism of how SARM1 is activated at lower NAD⁺ levels and causes NAD⁺ collapse and axon degeneration.

Three recent studies report cryo-EM structures of amyloid fibrils of islet amyloid polypeptide (IAPP), which are linked to type 2 diabetes (T2D) pathogenesis. The results shed light on the structural basis of IAPP fibril formation, reveal remarkable similarities between IAPP and Aβ fibrils and will inform the design of anti-amyloid drugs in T2D and Alzheimer’s disease (AD).

BAX and BAK oligomerize to mediate mitochondrial membrane permeabilization during apoptosis. A recent structure of the core domain of active BAK dimers with bound phospholipid molecules reveals a new bridging mechanism by which lipids drive BAX and BAK oligomerization and membrane pore formation.

In situ structures of the spirochete flagellar motor by cryo-ET reveal two distinct modes of interactions between the rotor ring and stator units. Together with new cryo-EM structures of the isolated stator units, this work provides insights into the mechanisms of torque generation and directional switch.

During translesion synthesis, eukaryotic DNA polymerase ζ carries out extension from a wide range of DNA lesions. Elucidation of the cryo-EM structure of polymerase ζ reveals how the enzyme catalyzes DNA strand synthesis beyond the lesion.

A new cryo-EM structure of mitochondrial complex I reveals ordered water molecules that connect key elements of the proton-translocating machinery. Analysis of the ubiquinone-binding site of complex I offers insights into the mechanism of catalytic turnover and the regulation of this essential metabolic enzyme.

Visualizing siRNA targeting of single mRNAs in living cells reveals that passing ribosomes temporarily unfold the mRNA, exposing it to siRNA recognition. This effect is due to the slow reorganization of many weak, suboptimal interactions within the mRNA.

The cell surface protein CD4 acts as a coreceptor for incoming HIV particles. However, the expression of CD4 in HIV-producing cells is detrimental to virus propagation and pathogenicity. To solve this issue, the viral accessory protein Nef forces CD4 endocytosis and targets it for lysosomal degradation. Structural elucidation of the AP-2–Nef–CD4 complex shows how Nef connects CD4 to the clathrin endocytic machinery, revealing a potential new target for anti-HIV therapy.

The nuclear piRNA pathway safeguards genome integrity in the germline by silencing transposable elements. Three recent studies have identified new players in the mammalian pathway. Two of these, TEX15 and SPOCD1, might provide a link between piRNA-guided complexes that recognize genomic targets and the molecular machinery that induces DNA methylation and transcriptional repression during mouse spermatogenesis.

Sfeir and colleagues consider recent insights into the pathways that process and repair damaged mitochondrial genomes, nuclear–mitochondrial cross-talk during mtDNA stress, and links between mtDNA dysfunction and innate immunity.

Translation and mRNA decay are tightly connected processes governing protein production, and their regulation involves an elaborate network of protein factors and sequence elements. A massively parallel RNA-based reporter system now reveals regulatory pathways triggered by 5′ UTR elements and allows dissection of the interplay between translation and mRNA decay.

Bivalent chromatin domains contain opposing histone modifications that assist cell lineage specification. Two studies report a role for Dppa2 and Dppa4 in the establishment of bivalency and the prevention of de novo DNA methylation at development-related genes in mouse embryonic stem cells.

Small molecules that hijack the cellular protein ubiquitination machinery to selectively degrade proteins of interest have emerged as therapeutic modalities and powerful research tools. This Review summarizes recent developments in this field, with a focus on the use of degraders as research tools.

Lauberth and Sartorelli consider and discuss recent insights into the biogenesis and function of enhancer RNAs and the key roles they play in the regulation of gene expression.

Cellular protein levels are finely tuned through microRNA-mediated gene regulation, triggered by RNA-induced silencing complexes (RISCs) that recognize, bind and silence mRNA targets. A recent study shows that, while mRNA target recognition is achieved with only about a third of the guide RNA sequence, formation of an efficient RISC conformation required for target silencing involves the coordination of transient structural states of the entire guide RNA–mRNA duplex.

The second Keystone Symposium on AAA+ proteins, “AAA+ Proteins: From Atomic Structures to Organisms”, was held in Tahoe City, USA in January 2020. The program highlighted recent advances from structural, biochemical and cellular approaches that have extended our understanding of these important ATP-driven molecular machines.

How Gram-negative bacteria transport glycerophospholipids between membranes remains a major point of inquiry for cell envelope biologists. Two groups report cryo-EM structures and functional studies of LetB (YebT), providing support for its involvement in cell envelope maintenance.

Cryptochrome (CRY) photoreceptors undergo photoresponsive homo-oligomerization to become physiologically active, and BICs (blue-light inhibitors of CRYs) suppress homo-oligomerization. Structural elucidation of CRY–CRY homo-oligomers and a CRY–BIC heterodimer reveals how the activity of plant CRYs is regulated by alternative protein–protein interactions.

Emerging evidence that telomere-specific Shelterin components also play roles in DNA replication timing within heterochromatin and genome maintenance suggests a potential common evolutionary origin of their protective and regulatory functions.