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AlphaFold’s success in protein structure predictions has led to similar attempts to predict interactomes. Here, the authors demonstrate that AI-based screens are very limited in discovering truly novel interactions compared to experimental screens, exposing open challenges in interaction prediction.

Loss of KRIT1 or CCM2 drives harmful KLF4 overexpression in brain vessels. Here, authors show a single KRIT1 must recruit two CCM2 proteins via dual PTB-NPxF interactions to suppress KLF4, revealing a previously unknown PTB clustering mechanism.

MEKK2, a member of the MAP3K family, plays a pivotal role in signaling cascades that regulate cellular responses such as proliferation, differentiation, and stress adaptation. Here the authors determine the crystal structure of the kinase domain of MEKK. Using a structure-directed approach they deconvolute the molecular basis of its autophosphorylation and its recruitment and phosphorylation of MAP2Ks, MEK5 and MKK6.

The bacterial pathway for fatty acid biosynthesis, FASII, is a target for development of new anti-staphylococcal drugs. Here, Morvan et al. show that exogenous fatty acids can favour the emergence of staphylococcal strains displaying resistance to multiple FASII inhibitors.

Cryo-EM data and functional assays reveal how the actin-cross-linking protein filamin A interacts with F-actin, rationalizing human disease mutations in molecular detail.

Tousled-like kinase 2 (TLK2) phosphorylates ASF1 histone chaperones to promote nucleosome assembly in S phase. Here, the authors show that TLK2 targets ASF1 by simulating its client protein histone H3, exploiting a primordial protein interaction surface for regulatory control.

Integrins are cell-surface adhesion receptors that are modulated by endo-exocytic trafficking, but existing tools to study this process can interfere with function. Here the authors develop β1 integrins carrying traceable tags in the extracellular domain; a pH-sensitive pHlourin tag or a HaloTag to facilitate dye attachment.

A SARS-CoV-2-human protein contactome map uncovers an inhibitor of viral replication.

Biosensors so far have mostly reported external traction forces exerted against the extracellular matrix or within adhesion receptors. Here, the authors present a sensor that reports molecular tension within the F-actin cytoskeleton.

A human binary protein interactome map that includes around 53,000 protein–protein interactions involving more than 8,000 proteins provides a reference for the study of human cellular function in health and disease.

CD8 + T cells are central players in anti-tumour immunity. Here authors identify Cul5, a ubiquitin E3 ligase as an important inhibitor of CD8 + T cell anti-tumour cytotoxicity and persistence via involvement with both T cell receptor and cytokine-regulated central pathways.

Maps of protein-protein interactions (PPIs) help identify new components of pathways, complexes, and processes. In this work, state-of-the-art methods are used to identify binary Drosophila PPIs, generating broadly useful physical and data resources.

Comprehensive mapping of binary protein-protein interactions requires to combine several complementary assays. Here, the authors show that complete coverage could be reached with a minimal number of assays as long as they explore various experimental conditions.

Crystal structures of integrin β5 tails with PAK4 reveal a unique interaction in which integrin β5 is not phosphorylated by PAK4 but rather inhibits PAK4 activity.

The ability of integrins to link the extracellular environment to intracellular networks enables cells to respond to chemical and physical cues. Insight has been gained into how talins and kindlins, two families of FERM-domain proteins that bind the cytoplasmic tail of integrins, mediate integrin activation and the cellular processes that depend on this.

Combining analysis of host proteome and transcriptome perturbations induced by tumour virus proteins with ongoing genome-wide studies of cancer facilitates the prioritization of cancer genes.

Autism spectrum disorder (ASD) is a complex genetic trait that encompasses a range of neurodevelopmental disorders. Here, the authors clone brain-expressed alternatively-spliced isoforms of ASD risk factors and construct a network of protein interactions that provides further insight into the disease aetiology.

CRISPR/Cas systems are bacterial adaptive immune systems that provide sequence-specific protection from invading nucleic acids, including from bacteriophages; in a notable reverse a vibriophage-encoded CRISPR/Cas system, used to disable a bacteriophage inhibitory chromosomal island in Vibrio cholerae, is identified.

Most human protein-coding genes are expressed as multiple isoforms. Here the authors present ORF Capture-seq that uses cloned ORFs as probes to capture and sequence full length transcript sequences. This enables highly sensitive characterization of eukaryotic transcriptomes.

The risk of developing active tuberculosis (TB) in individuals with latent TB infection is highly variable within and among different risk groups. A personalized risk predictor was developed to better target preventative treatment to individuals at greatest risk, supporting evidence-based clinical decision-making for latent TB.

Cell surface acidification has key roles in both cell migration and bone resorption. A study now identifies a pathway whereby growth factor signalling induces local acidification, driving sialic acid removal and galectin-3-mediated integrin internalization.

Current understanding of Long COVID is limited, in part, due to lack of evidence from population-representative studies. Here, the authors analyse data from ten UK population-based studies and electronic health records, and find wide variation in the frequency of Long COVID between studies but some consistent risk factors.

HLA-B*57:01 restricted EBV-specific T-cell receptor specificity is altered by abacavir, suggesting a potentially inhibitory effect of abacavir on HLA-B*57:01 restricted TCR recognition.

Identification of disease modules in the human interactome can guide more efficacious therapeutic selections. Here, the authors introduce a network-based methodology to identify individualized disease modules by mapping patients’ DNA and RNA sequencing profiles to the interactome, enabling prediction of cancer type-specific drug responses.

The protein TRIM28 is identified as a factor that modulates RNA polymerase II pausing and transcriptional elongation at a large number of mammalian genes. This function is regulated by transcription-coupled phosphorylation of TRIM28 at Ser824.

Urra et al. discover that IRE1α, an ER stress mediator, interacts with filamin A and controls actin dynamics and cell migration in mouse, Drosophila and zebrafish models in a manner independent of its canonical function.

Cell–extracellular matrix (ECM) interactions occur at specialized, multi-protein adhesion complexes, with clustered integrins as the predominant ECM receptors. Progress in characterization of adhesion composition, organization and dynamics in response to force has improved understanding of adhesion maturation and turnover and the relationships between adhesion structures and functions.

The physical link between integrin adhesion receptors and the actin cytoskeleton mediates bidirectional transmission of force and biochemical signals across the plasma membrane. This link is essential for the development and function of multicellular animals. Recent work reveals that the integrin-associated actin-binding protein talin provides the initial connections between integrins and the cytoskeleton, establishing a pivotal role for this connection in bi-directional integrin signalling.

The Impact of Genomic Variation on Function Consortium is combining single-cell mapping, genomic perturbations and predictive modelling to investigate relationships between human genomic variation, genome function and phenotypes and will provide an open resource to the community.

Using a chimaeric integrin α₅ (where the tail is replaced by that of α₂), Yun et al. show that in endothelial cells, integrin α₅ interacts with the cAMP-specific phosphodiesterase PDE4D5 to reduce cAMP levels and inflammation both in vitro and in vivo.