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Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction, intracellular transport, and protein degradation, it became an interesting target for cancer therapy. Structurally, Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function, Hsp90 works together with a large group of cofactors, termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90, which facilitate the maturation of client proteins. In addition, posttranslational modifications of Hsp90, such as phosphorylation and acetylation, provide another level of regulation. They influence the conformational cycle, co-chaperone interaction, and inter-domain communications. In this review, we discuss the recent progress made in understanding the Hsp90 machinery.

Ribosome is responsible for protein synthesis in all organisms and ribosomal proteins (RPs) play important roles in the formation of a functional ribosome. L11 was recently shown to regulate p53 activity through a direct binding with MDM2 and abrogating the MDM2-induced p53 degradation in response to ribosomal stress. However, the studies were performed in cell lines and the significance of this tumor suppressor function of L11 has yet to be explored in animal models. To investigate the effects of the deletion of L11 and its physiological relevance to p53 activity, we knocked down the rpl11 gene in zebrafish and analyzed the p53 response. Contrary to the cell line-based results, our data indicate that an L11 deficiency in a model organism activates the p53 pathway. The L11-deficient embryos (morphants) displayed developmental abnormalities primarily in the brain, leading to embryonic lethality within 6-7 days post fertilization. Extensive apoptosis was observed in the head region of the morphants, thus correlating the morphological defects with apparent cell death. A decrease in total abundance of genes involved in neural patterning of the brain was observed in the morphants, suggesting a reduction in neural progenitor cells. Upregulation of the genes involved in the p53 pathway were observed in the morphants. Simultaneous knockdown of the p53 gene rescued the developmental defects and apoptosis in the morphants. These results suggest that ribosomal dysfunction due to the loss of L11 activates a p53-dependent checkpoint response to prevent improper embryonic development.

Objective To investigate the association between ASF1B expression and pathological characteristics of breast cancer, and to further explore its role in tumor progression and the immune microenvironment, thereby evaluating its potential as a therapeutic target. Methods ASF1B expression in breast cancer was analyzed using the GEPIA2 and BEST databases. Its association with patient prognosis was assessed using Kaplan–Meier survival analysis. Protein co‐expression networks were constructed using GeneMANIA. The correlation between ASF1B expression and immune cell infiltration was evaluated through the TIMER platform. Experimental validation was performed using qPCR and immunohistochemistry (IHC) on 67 breast cancer tissue samples. Results ASF1B expression was significantly elevated in breast cancer tissues compared to normal tissues (p < 0.05). High ASF1B expression was associated with reduced overall and recurrence‐free survival (p < 0.05). Protein interaction analysis revealed that ASF1B was strongly linked to proteins involved in DNA replication, cell cycle progression, and chromatin remodeling. Immune analysis indicated positive correlations with B cells, neutrophils, and dendritic cells and a negative correlation with macrophage infiltration (p < 0.05). Clinical data further showed that high ASF1B expression was significantly associated with HER2‐positive breast cancer (p = 0.026). Conclusion ASF1B is highly expressed in breast cancer and correlates with poor prognosis and immune cell infiltration. It may serve as a potential prognostic biomarker and therapeutic target in breast cancer.

Background One of the main issues in the automated protein function prediction (AFP) problem is the integration of multiple networked data sources. The UNIPred algorithm was thereby proposed to efficiently integrate —in a function-specific fashion— the protein networks by taking into account the imbalance that characterizes protein annotations, and to subsequently predict novel hypotheses about unannotated proteins. UNIPred is publicly available as R code, which might result of limited usage for non-expert users. Moreover, its application requires efforts in the acquisition and preparation of the networks to be integrated. Finally, the UNIPred source code does not handle the visualization of the resulting consensus network, whereas suitable views of the network topology are necessary to explore and interpret existing protein relationships. Results We address the aforementioned issues by proposing UNIPred-Web, a user-friendly Web tool for the application of the UNIPred algorithm to a variety of biomolecular networks, already supplied by the system, and for the visualization and exploration of protein networks. We support different organisms and different types of networks —e.g., co-expression, shared domains and physical interaction networks. Users are supported in the different phases of the process, ranging from the selection of the networks and the protein function to be predicted, to the navigation of the integrated network. The system also supports the upload of user-defined protein networks. The vertex-centric and the highly interactive approach of UNIPred-Web allow a narrow exploration of specific proteins, and an interactive analysis of large sub-networks with only a few mouse clicks. Conclusions UNIPred-Web offers a practical and intuitive (visual) guidance to biologists interested in gaining insights into protein biomolecular functions. UNIPred-Web provides facilities for the integration of networks, and supplies a framework for the imbalance-aware protein network integration of nine organisms, the prediction of thousands of GO protein functions, and a easy-to-use graphical interface for the visual analysis, navigation and interpretation of the integrated networks and of the functional predictions.

The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 Å resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N -linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N -linked glycan and tolerance for epitope-sequence variation. A crystal structure of the human immunodeficiency virus Env trimer, used by the virus to infect cells, is determined here; the new structure, which shows the pre-fusion form of Env, increases our understanding of the fusion mechanism and of how the conformation of Env allows the virus to evade the immune response. Structural basis for HIV-1 immune evasion Peter Kwong and colleagues provide a new crystal structure of the human immunodeficiency virus type 1 (HIV-1) Env trimer, part of the type I fusion machine that facilitates virus entry into cells by interacting with host cellular receptors and fusing membranes of virus and host cell. The Env trimer consists of three gp120 and three gp41 subunits. The structure, at 3.5 Å resolution, shows the pre-fusion form of Env and allows the conformation of the gp41 subunits to be resolved, thereby increasing our understanding of how the trimer functions to enable fusion and how it evades recognition by the immune response. This evasion is, to a large degree, responsible for the difficulty in developing an effective HIV-1 vaccine.

Rational protein engineering requires a holistic understanding of protein function. Here, we apply deep learning to unlabeled amino-acid sequences to distill the fundamental features of a protein into a statistical representation that is semantically rich and structurally, evolutionarily and biophysically grounded. We show that the simplest models built on top of this unified representation (UniRep) are broadly applicable and generalize to unseen regions of sequence space. Our data-driven approach predicts the stability of natural and de novo designed proteins, and the quantitative function of molecularly diverse mutants, competitively with the state-of-the-art methods. UniRep further enables two orders of magnitude efficiency improvement in a protein engineering task. UniRep is a versatile summary of fundamental protein features that can be applied across protein engineering informatics.

A central tenet of biology is that globular proteins have a unique 3D structure under physiological conditions. Recent work has challenged this notion by demonstrating that some proteins switch folds, a process that involves remodeling of secondary structure in response to a few mutations (evolved fold switchers) or cellular stimuli (extant fold switchers). To date, extant fold switchers have been viewed as rare byproducts of evolution, but their frequency has been neither quantified nor estimated. By systematically and exhaustively searching the Protein Data Bank (PDB), we found ∼100 extant fold-switching proteins. Furthermore, we gathered multiple lines of evidence suggesting that these proteins are widespread in nature. Based on these lines of evidence, we hypothesized that the frequency of extant fold-switching proteins may be underrepresented by the structures in the PDB. Thus, we sought to identify other putative extant fold switchers with only one solved conformation. To do this, we identified two characteristic features of our ∼100 extant fold-switching proteins, incorrect secondary structure predictions and likely independent folding cooperativity, and searched the PDB for other proteins with similar features. Reassuringly, this method identified dozens of other proteins in the literature with indication of a structural change but only one solved conformation in the PDB. Thus, we used it to estimate that 0.5–4% of PDB proteins switch folds. These results demonstrate that extant fold-switching proteins are likely more common than the PDB reflects, which has implications for cell biology, genomics, and human health.

Many proteins and protein segments cannot attain a single stable three-dimensional structure under physiological conditions; instead, they adopt multiple interconverting conformational states. Such intrinsically disordered proteins or protein segments are highly abundant across proteomes, and are involved in various effector functions. This review focuses on different aspects of disordered proteins and disordered protein regions, which form the basis of the so-called “Disorder–function paradigm” of proteins. Additionally, various experimental approaches and computational tools used for characterizing disordered regions in proteins are discussed. Finally, the role of disordered proteins in diseases and their utility as potential drug targets are explored.

Moths use pheromones to ensure intraspecific communication. Nevertheless, few studies are focused on both intra- and intersexual communication based on pheromone recognition. Pheromone-binding proteins (PBPs) are generally believed pivotal for male moths in recognizing female pheromones. Our research revealed that PBP1 of Agriphila aeneociliella (AaenPBP1) serves a dual function in both intra- and intersexual pheromone recognition. Here, a total of 20 odorant-binding protein (OBP) family genes from A. aeneociliella were identified and subjected to transcriptional analysis. Among these, AaenPBP1 was primarily highly expressed in the antennae. Competitive fluorescence binding assays and molecular docking analyses demonstrated that AaenPBP1 exhibits a strong binding affinity for the female sex pheromone (Z)-9-Hexadecenyl acetate and the male pheromone 1-Nonanal. Notably, hydrogen bonds were observed between Ser56 and the ligands. The analysis of pheromone components and PBPs in lepidopteran lineage suggested that their strong and precise interactions, shaped by coevolution, may play a crucial role in facilitating reproductive isolation in moths. Our findings provide valuable insight into the functional significance of PBPs in invertebrates and support the development of behavioral regulation tools as part of an integrated pest management strategy targeting crambid pests.

Interpreting variants of uncertain significance (VUS) is a central challenge in medical genetics. One approach is to experimentally measure the functional consequences of VUS, but to date this approach has been post hoc and low throughput. Here we use massively parallel assays to measure the effects of nearly 2000 missense substitutions in the RING domain of BRCA1 on its E3 ubiquitin ligase activity and its binding to the BARD1 RING domain. From the resulting scores, we generate a model to predict the capacities of full-length BRCA1 variants to support homology-directed DNA repair, the essential role of BRCA1 in tumor suppression, and show that it outperforms widely used biological-effect prediction algorithms. We envision that massively parallel functional assays may facilitate the prospective interpretation of variants observed in clinical sequencing.