Biology subjects

Han, B.

Publications and source records attributed to Han, B..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Earlier finish of motor planning in the premotor cortex predicts faster motor command in the primary motor cortex: human intracranial EEG evidence

The human motor system has a hierarchical control during finger movements. The non-primary motor cortex (premotor cortex, PM, and supplementary motor area, SMA) organizes motor planning, while the primary motor cortex (M1) is responsible for motor execution. We utilized the human intracranial EEGs high temporal and spatial resolution to investigate how the temporal dynamics of the high-gamma neural oscillations in the hierarchically organized motor sub-regions, during both pre-movement planning and motor execution, correlated with reaction times (RTs) in a cued finger movement task. Our results showed that the high-gamma power of PM, SMA, and M1 activated sequentially. More importantly, the sustained high-gamma power activation in the non-primary motor cortex and the peak latency of high-gamma power in M1 had a significant predictive relationship with the RTs. In particular, the faster the activation of the non-primary motor cortex returned to baseline, the faster the motor command in M1, and accordingly the shorter the RTs. Further, pairwise phase coherence between the motor areas showed that the more sustained the connection between the motor areas, the longer the RTs would be. The current findings illustrate the relationship between the temporal profiles of high-gamma power in human motor areas and response performance.

neuroscience↗

bioRxiv2024

Differences in milk microbiota between healthy cows and cows with recurring Klebsiella mastitis

Klebsiella spp. infections continue to have a significant economic impact on the dairy industry, being an important cause of severe clinical mastitis, recurrent infections, and demonstrating poor response to antimicrobials. It is, therefore, essential to investigate the underlying causes of Klebsiella spp. infections. Here we used high-throughput DNA sequencing to characterize the milk microbiota of healthy dairy cows (HDC) and cows with history of recurrent Klebsiella mastitis (KLB). Our goal was to identify potential pathogenic genera associated with recurrent Klebsiella infections in cows. The relative abundance of Firmicutes and Faecalibacterium was greater in the KLB group than in the HDC group. In contrast, Proteobacteria and Labrenzia were less abundant than in the HDC group. Although the species distributions differed between groups, diversity and abundance of communities were comparable. Notably, genera of increased occurrence in the KLB group were mostly intestinal-associated, which suggests that cows in the KLB group resided in a contaminated environment or had increased teat-end exposure to fecal bacteria. We did not detect major differences in microbiota among quarters, and also between fore-strip milk and milk collected after fore-stripping. Conversely, milk of heifers had increased alpha diversity in comparison to milk of multiparous cows.

microbiology↗

bioRxiv2024

Auditory stimuli extend the temporal window of visual integration by modulating alpha-band oscillations

In multisensory environments, signals from different modalities interact to shape perception, but the underlying temporal dynamics remain unclear. We investigated how a brief auditory stimulus affects the temporal integration of successive visual events using electroencephalography (EEG). Participants viewed two consecutive flashes, with or without an auditory beep accompanying the first flash, and reported whether they perceived one or two flashes. The beep shifted the psychometric fusion threshold to longer interstimulus intervals, indicating a wider temporal integration window. This behavioural shift was accompanied by a transient reduction in poststimulus instantaneous alpha frequency, and individual differences in alpha-cycle lengthening correlated with threshold prolongation. Auditory input also weakened the relationship between prestimulus alpha frequency and perceptual report while strengthening the corresponding relationship with prestimulus alpha phase. In a follow-up transcranial alternating current stimulation (tACS) experiment, the effects of lower- versus upper-alpha stimulation on fusion thresholds differed between the visual-only and audiovisual conditions. A computational model based on phase resetting and perceptual cycles qualitatively reproduced the main findings. Together, the results suggest that a brief sound can reorganize alpha-band timing and thereby widen the temporal window of visual integration.

neuroscience↗

bioRxiv2023

Environmental and ecological signals predict periods of nutritional stress for Eastern Australian flying fox populations.

Food availability determines where animals use space across a landscape and therefore affects the risk of encounters that lead to zoonotic spillover. This relationship is evident in Australian flying foxes (Pteropus spp; fruit bats), where acute food shortages precede clusters of Hendra virus spillovers. Using explainable artificial intelligence, we predicted months of food shortages from climatological and ecological covariates (1996-2022) in eastern Australia. Overall accuracy in predicting months of low food availability on a test set from 2018 up to 2022 reached 93.33% and 92.59% based on climatological and bat-level features, respectively. Seasonality and Oceanic El Nino Index were the most important environmental features, while the number of bats in rescue centers and their body weights were the most important bat-level features. These models support predictive signals up to nine months in advance, facilitating action to mitigate spillover risk.

ecology↗

bioRxiv2023

Perivascular Excitation Tunnelling: a Novel and Preventable Cause of Cardiac Reperfusion Arrhythmias

BackgroundReperfusion after myocardial ischaemia can lead to deadly arrhythmias, in part due to heterogeneities in electrophysiology (EP) across affected tissue. There is a need to understand the spatiotemporal dynamics of ischaemia-reperfusion arrhythmias (IRA), so that reperfusion strategies to prevent them can be found. MethodsLangendorff-perfused rabbit isolated hearts were loaded with a voltage-sensitive dye. Epifluorescence imaging was used to track action potential propagation across the cardiac surface. The heart was simultaneously perfused globally (via the aorta) and locally (via cannulation of a single coronary artery) with an oxygenated physiological saline solution. Local perfusion was subsequently switched to and from solutions that mimic aspects of ischaemia (acidosis, hypoxia, hyperkalaemia, or a simulated ischaemia solution combining all three) or to no-flow. Subsequently, different reperfusion strategies were tested to reduce IRA re-entries. The most successful strategy for preventing re-entry was tested in Langendorff-perfused isolated pig hearts to assess the clinical relevance of the observed mechanism and treatment strategy. ResultsUpon sudden reperfusion of the cannulated coronary artery in rabbit hearts we observed a preferential recovery of electrical excitability along the vessels main branch ( perivascular excitation tunnelling, PVET). This resulted in re-entry in roughly half of the hearts. Hyperkalaemia and hypoxia, but not acidosis, were sufficient to lead to conduction block, PVET, and re-entry, with both PVET and re-entry more frequently observed after hyperkalaemia than hypoxia. PVET was also present in pigs and PVET-based re-entries were successfully prevented in rabbit and pig hearts by two-step reperfusion, first of the distal majority of the previously ischaemic region, and then of the remaining tissue from the proximal point. With this strategy, any PVET that developed in the distal tissue was blocked by the still inexcitable proximal tissue. Upon reperfusion of the proximal tissue, there was a reduced path length for PVET. As a consequence, the associated excitable gap was too short for re-entrant excitation. ConclusionsWe observed a novel arrhythmia mechanism upon coronary reperfusion (PVET), which suggests that preferential recovery of myocardial excitability along the reperfused vessel is an important mechanism underlying IRA formation. PVET-induced re-entry reliably occurred in both rabbit and pig hearts and could be prevented by two-step reperfusion. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=171 HEIGHT=200 SRC="FIGDIR/small/569031v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@139a095org.highwire.dtl.DTLVardef@5dc811org.highwire.dtl.DTLVardef@f9db75org.highwire.dtl.DTLVardef@1b6f66b_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2023

High clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue

Somatic copy number alterations (SCNAs) are pervasive in advanced human cancers, but their prevalence and spatial distribution in early-stage, localized tumors and their surrounding normal tissues are poorly characterized. Here, we performed multi-region, single-cell DNA sequencing to characterize the SCNA landscape across multiple tumor-rich and normal tissue regions ([~]125 mm3 tissue cubes) obtained from prostatectomy performed in two patients with localized prostate cancer. We identified two distinct populations of cells with abnormal karyotypes, one marked by sparse deletions or amplifications ( pseudo-diploid cells) and the second characterized by genome-wide copy number changes reminiscent of monster cells previously described in colorectal cancer. Pseudo-diploid cells formed numerous small-sized subclones ranging from highly spatially localized to broadly spread subclones mainly featuring (sub-)chromosomal arm deletions. In contrast, monster cells harbored whole-chromosome gains and losses and were mostly singular events detected throughout the prostate, including normal tissue regions. Targeted deep sequencing of cancer-associated genes revealed a more confined pattern of mutations overlapping with tumor-rich regions, although we also detected mutations in regions deemed normal based on morphological assessment and bulk RNA-seq. Highly localized pseudo-diploid subclones were confined within tumor-rich regions and typically carried deletions involving chromosome (chr) 6 and 13, resulting in simultaneous loss of multiple tumor-suppressor genes, including FOXO1 and FOXO3 encoding two transcription factors belonging to the Forkhead family previously implicated in prostate carcinogenesis. Tumor-rich regions also contained mutations in genes frequently mutated in prostate cancer, including FOXA1, LRP1B, SPOP, and SPTA1. Our study reveals that SCNAs are widespread in both normal and tumor regions across the prostate gland of patients with localized prostate cancer and suggests that a subset of pseudo-diploid cells harboring chromosomal deletions that result in the loss of specific tumor-suppressor genes drive tumorigenesis in the aging prostate.

cancer biology↗

bioRxiv2023

Unbiased phosphoproteomics analysis unveils modulation of insulin signaling by extramitotic CDK1 kinase activity in human myotubes

Sensitivity and plasticity of insulin signaling and glucose uptake in skeletal muscle depends on determinants such as genetic variation and obesity. We collected muscle biopsies and isolated myoblasts from a multi-ethnic cohort of lean South Asians (N=10), lean Chinese (N=10), and obese Chinese (N=10), and analysed the proteome and phosphoproteome dynamics in terminally differentiated myotubes after a low-dose insulin stimulation (10nM at 0, 5, 30 min). The myotubes initially responded with increased abundance and phosphorylation level changes along the PI3K/AKT/mTOR axis, decreased abundance of translation initiation factors, and increased phosphorylation levels on proteins involved in mRNA processing at 5 min. After the acute response, protein abundance returned to baseline at 30 min, while phosphorylation changes persisted in proteins including AKT, RPS6 and AS160 (TBC1D4). A joint kinase-substrate statistical analysis revealed that protein abundance changes of AKT, PAK1 and CDK1 showed concordant phosphorylation changes in their respective substrates upon insulin stimulation. We also observed increased phosphorylation of some substrates uniquely in each group, particularly the substrates of CDKs showing stronger changes in South Asians than in Chinese. Pharmacological inhibition and siRNA knockdown of CDK1, a non-myogenic kinase, in terminally differentiated myotubes reduced glucose uptake and desensitized several phosphorylation-mediated signaling on protein translation initiation factors, IRS1, and AS160. Our data suggest that basal extramitotic activity of CDK1 is required for PI3K/AKT/mTORC1 signaling cascade and glucose uptake in insulin-stimulated myotubes. The data also provide a rich resource for studying the role of other kinases in the mechanism of insulin resistance in human myotubes.

physiology↗

bioRxiv2023

Microsporidia dressing up: the spore polaroplast transport through the polar tube and transformation into the sporoplasm membrane

Microsporidia are obligate intracellular parasites that infect a wide variety of hosts, including humans. Microsporidian spores possess a unique, highly specialized invasion apparatus involving the polar filament, polaroplast and posterior vacuole. During spore germination, the polar filament is discharged out of the spore forming the hollow polar tube that transports the sporoplasm components including nucleus into the host cell to achieve the invasion. Due to the complicated topological changes occurring in this process, the formation of sporoplasm is unclear. Here, electron microscopy observation and DiI staining confirmed that during spore germination, a large number of vesicles derived from the polaroplast, nucleus and other cytoplasm were transported out via the polar tube. Meanwhile, the posterior vacuole and plasma membrane remained in the empty spore coat. In addition, there was no DiI-labeled membrane around the nucleus in mature spores, whereas a DiI-labeled limit membrane wrapping nucleus was found at the tip of the extruded polar tube, suggesting that the membrane of sporoplasm was formed outside the mature spore. Two Nosema bombycis sporoplasm surface proteins (NbTMP1 and NoboABCG1.1) were located at the polaroplast in mature spores, in the extruded polar tube and on the sporoplasm membrane, which indicated that the polaroplast transported via the polar tube finally became the limiting membrane of the sporoplasm. Golgi-tracker green and Golgi marker protein syntaxin 6 were also found the same model, which was consistent with the transported polaroplast derived from Golgi transformed into the novel sporoplasm membrane during spore germination. ImportanceMicrosporidia, obligate intracellular pathogenic organisms, cause huge economic losses in agriculture and even threaten human health. The key to successful infection of microsporidia is its unique invasion apparatus which includes the polar filament, polaroplast and posterior vacuole. When the spore is activated to geminate, the polar filament uncoils and undergoes a rapid transition into the hollow polar tube that will transport the sporoplasm components including nucleus into a host cell to achieve the invasion. Knowledge of structure difference between polar filament and polar tube, the process of cargo transport in extruded polar tube, and the formation of the sporoplasm membrane are still poorly understood. Herein, we verify that the polar filament evaginates to form the polar tube, which serves as a conduit for transporting elongated nucleus and other sporoplasm components. And we confirm that the transported polaroplast finally transforms into the novel sporoplasm membrane during spore germination. Our study provides new insights into the cargo transportation process of polar tube and origin of the sporoplasm membrane, which serve as foundations for clarifying the microsporidian infection mechanism.

pathology↗

bioRxiv2023

The maize PLASTID TERMINAL OXIDASE (PTOX) gene controls the carotenoid content of kernels.

O_LICarotenoids perform a broad range of important functions in humans; therefore, carotenoid biofortification of maize (Zea mays L.), one of the most highly produced cereal crops worldwide, would have a global impact on human health. C_LIO_LIPLASTID TERMINAL OXIDASE (PTOX) genes play an important role in carotenoid metabolism; however, the possible function of PTOX in carotenoid biosynthesis in maize has not yet been explored. In this study, we identified the maize PTOX gene ZmPTOX1 by forward genetic screening. C_LIO_LIWhile most higher plant species possess a single copy of the PTOX gene, maize carries two tandemly duplicated copies of ZmPTOX. Characterization of Zmptox1 mutants revealed that disrupting one copy of ZmPTOX1 was enough to impair carotenoid biosynthesis, indicating that ZmPTOX1 is essential for carotenoid biosynthesis in maize kernels. Remarkably, overexpression of ZmPTOX1 significantly improved the content of carotenoids, especially {beta}-carotene (provitamin A), which was increased by ~3-fold, in maize kernels. C_LIO_LIOverall, our study shows that ZmPTOX1 plays a crucial role in carotenoid biosynthesis in maize kernels and suggests that fine-tuning the expression of this gene could improve the nutritional value of cereal grains. C_LI

plant biology↗

bioRxiv2023

Why do cell-level test methods for detecting differentially expressed genes fail in single-cell RNA-seq data?

Large-scale multi-subject single-cell data have become very common. For differential gene expression (DGE) analysis of these datasets, a common practice is to choose any of the two: pseudobulk methods or cell-wise methods. However, multi-subject single-cell studies have highly heterogeneous study designs. Some studies have case/control samples to be compared and tested, and some make within-sample perturbations. In this work, we report that to prevent severely inflated errors, we must treat the two categories of study designs differently in the DGE analysis. In studies with case/control labels, pseudobulk methods work the best, and cell-wise methods produce severe inflation of type II errors. Cell-wise methods work best in studies with within-sample perturbations, and pseudobulk methods produce severe inflation of type I errors. We provide mathematical proofs to support this argument. Surprisingly, many existing studies, even published ones, often choose an inappropriate DGE method. The most common temptation is to use cell-wise methods for case/control studies, which will only make p-values falsely look significant. Our analyses and proofs warn that choosing an appropriate DGE method is not an option but a requirement.

genomics↗

bioRxiv2022

Design principles of caveolins across metazoa and beyond

Caveolins are a unique family of membrane-remodeling proteins present broadly across animals (Metazoa), and in vertebrates form flask-shaped invaginations known as caveolae. While human caveolin-1 assembles into an amphipathic disc composed of 11 spirally packed protomers, the structural basis underlying caveolin function across animals remains elusive. Here, we predicted structures for 73 caveolins spanning animal diversity, as well as a newly identified choanoflagellate caveolin from Salpingoeca rosetta, a unicellular relative to animals. This analysis revealed seven conserved structural elements and a propensity to assemble into amphipathic discs. Despite extreme sequence variability, new cryo-EM structures of caveolins from the choanoflagellate and the purple sea urchin Strongylocentrotus purpuratus exhibit striking structural similarities to human caveolin-1, validating the structural predictions. Lastly, tracing the chromosomal evolutionary history of caveolins revealed evolutionary branches where caveolins translocated and expanded, including a parahoxozoan ancestral chromosome as the origin of most caveolin diversity. These results show that caveolins possess an ancient structural framework predating Metazoa and provide a new structural paradigm to explore the molecular basis of caveolin function across diverse evolutionary lineages.

biophysics↗

bioRxiv2022

7SK methylation Promotes Transcriptional Activity upon Growth Factor Stimulation

A fundamental facet of cell signaling is the conversion of extracellular signals into adaptive transcriptional responses. The role of RNA modifications in this process is poorly understood. The small nuclear RNA 7SK prevents transcription elongation by sequestering the complex CDK9/CCNT1 (P-TEFb). We discovered that METTL3 methylates 7SK. The m6A methylation of 7SK in turn promotes its binding to heterogeneous nuclear ribonucleoproteins (HNRNPs), with consequent release of the HEXIM1/P-TEFb complex - leading to the induction of growth factor-stimulated transcriptional responses. The methylation of 7SK relies on the activation of METTL3 via phosphorylation downstream of growth factors-signaling pathways such as the epidermal growth factor (EGF). Our findings establish a novel function for the m6A modification in converting growth-factor signaling events to a transcriptional elongation regulatory response via an RNA-methylation-dependent switch. One-Sentence Summarym6A methylation of the non-coding RNA 7SK promotes transcriptional activity upon growth factor stimulation.

molecular biology↗

bioRxiv2022

Molecular insights into the Darwin paradox of coral reefs from the sea anemone Aiptasia

Symbiotic cnidarians such as corals and anemones form highly productive and biodiverse coral-reef ecosystems in nutrient-poor ocean environments, a phenomenon known as Darwins Paradox. Resolving this paradox requires elucidating the molecular bases of efficient nutrient distribution and recycling in the cnidarian-dinoflagellate symbiosis. Using the sea anemone Aiptasia, we show that during symbiosis, the increased availability of glucose and the presence of the algae jointly induce the coordinated upregulation and re-localization of glucose and ammonium transporters. These molecular responses are critical to support symbiont functioning and organism-wide nitrogen assimilation through GS/GOGAT-mediated amino-acid biosynthesis. Our results reveal crucial aspects of the molecular mechanisms underlying nitrogen conservation and recycling in these organisms that allow them to thrive in the nitrogen-poor ocean environments. One-sentence summaryWhole-organism nitrogen assimilation fueled by glucose from symbiotic algae enables corals to flourish in oligotrophic waters.

molecular biology↗

bioRxiv2022

A statistical genetics guide to identifying HLA alleles driving complex disease

The human leukocyte antigen (HLA) locus is associated with more human complex diseases than any other locus. In many diseases it explains more heritability than all other known loci combined. Investigators have now demonstrated the accuracy of in silico HLA imputation methods. These approaches enable rapid and accurate estimation of HLA alleles in the millions of individuals that are already genotyped on microarrays. HLA imputation has been used to define causal variation in autoimmune diseases, such as type I diabetes, and infectious diseases, such as HIV infection control. However, there are few guidelines on performing HLA imputation, association testing, and fine-mapping. Here, we present comprehensive statistical genetics guide to impute HLA alleles from genotype data. We provide detailed protocols, including standard quality control measures for input genotyping data and describe options to impute HLA alleles and amino acids including a web-based Michigan Imputation Server. We updated the HLA imputation reference panel representing global populations (African, East Asian, European and Latino) available at the Michigan Imputation Server (n = 20,349) and achived high imputation accuracy (mean dosage correlation r = 0.981). We finally offer best practice recommendations to conduct association tests in order to define the alleles, amino acids, and haplotypes affecting human traits. This protocol will be broadly applicable to the large-scale genotyping data and contribute to defining the role of HLA in human diseases across global populations.

genetics↗

bioRxiv2022

Comparative genomic analyses of Lactococcus garvieae isolated from bovine mastitis in China

Lactococcus garvieae is an emerging zoonotic pathogen, but there are few reports regarding bovine mastitis. The recent prevalence of L. garvieae poses an increasing disease threat and global public health risk. A total of 39 L. garvieae isolates were obtained from 2899 bovine clinical mastitis milk samples in 6 provinces of China from 2017 to 2021. Five clonal complexes were determined from 32 MLST types of L. garvieae; ST46 was the predominant sequence type and 13 novel MLST types were identified. All isolates were resistant to chloramphenicol and clindamycin, but susceptible to penicillin, ampicillin, amoxicillin-clavulanic acid, imipenem, ceftiofur, enrofloxacin, and marbofloxacin. Based on genomic analyses, L. garvieae had 6310 genes, including 1015, 3641 and 1654 core, accessory and unique genes. All isolates had virulence genes coding for collagenase, fibronectin-binding protein, Glyceraldehyde-3-phosphate dehydrogenase, superoxide dismutase and NADH oxidase. Most isolates had lsaD and mdtA AMR genes. Based on COG results, the functions of defense, transcription and replication, recombination and repair were enhanced in unique genes, whereas functions of translation, ribosomal structure and biogenesis were enhanced in core genes. The KEGG functional categories enriched in unique genes included human disease and membrane transport, whereas COG functional categories enriched in core genes included energy metabolism, nucleotide metabolism and translation. No gene was significantly associated with host specificity. In addition, core genome SNPs analysis suggested potential host adaptation of some isolates in several sequence types. Therefore, this study characterized L. garvieae isolated from mastitis and assessed host adaptation of L. garvieae to various hosts. IMPORTANCEThis study provides important insights on bovine mastitis key topic pathogen Lactococcus garvieae, which constitutes mastitis concerns. However, comprehensive genomic analyses of L. garvieae from dairy farms have not been performed. This study gives a detailed and comprehensive novel feature in L. garvieae, an important but poorly characterized bacterium, recovered in the past 5 years in 6 Chinese provinces. We documented diverse contributory genetic processes, including predominant sequence type ST46 and 13 novel MLST types. L. garvieae had 6310 genes, including 1015, 3641 and 1654 core, accessory and unique genes. All isolates had virulence genes coding for collagenase, fibronectin-binding protein, Glyceraldehyde-3-phosphate dehydrogenase, superoxide dismutase and NADH oxidase, and resistant to chloramphenicol and clindamycin. Most isolates had lsaD and mdtA antimicrobial resistance genes. No gene was significantly associated with host specificity. This is the first absolute quantification of L. garvieae isolated from mastitis and identified host adaptation of L. garvieae to various hosts.

microbiology↗

bioRxiv2022

Template-free prediction of a new protein fold and oligomeric assembly by Alphafold2

AlphaFold2 (AF2) has revolutionized the field of protein structural prediction. Here, we test its ability to predict the tertiary and quaternary structure of a previously undescribed scaffold with new folds and unusual architecture, the monotopic membrane protein caveolin-1 (CAV1). CAV1 assembles into a disc-shaped oligomer composed of 11 symmetrically arranged protomers, each assuming an identical new fold, and contains the largest parallel {beta}-barrel known to exist in nature. Remarkably, AF2 predicts both the fold of the protomers and interfaces between them. It also assembles between 7 and 15 copies of CAV1 into disc-shaped complexes. However, the predicted multimers are energetically strained, especially the parallel {beta}-barrel. These findings highlight the ability of AF2 to correctly predict new protein folds and oligomeric assemblies at a granular level while missing some elements of higher order complexes, thus positing a new direction for the continued development of deep learning protein structure prediction approaches.

biophysics↗

bioRxiv2022

Social Regulation of Egg Size Plasticity in the Honey Bee is Mediated by Cytoskeleton Organizer Rho1

Egg size plasticity represents an adaptive reproductive strategy in numerous organisms, including the honey bee, Apis mellifera. However, the proximate causation of this plasticity and egg size in general is unknown. We show that honey bee queens predictably and reversibly adjust egg size in response to their colony size and that this plasticity is an active response to the queens perception of colony size instead of a consequence of egg laying rate. The egg size increase involves changes of 290 ovarian proteins, mostly related to increased energy metabolism, protein transport, and cytoskeleton functions. Spatio-temporal expression analysis of the small GTPase Rho1 indicates its central role in egg size regulation, which we confirm by RNAi-mediated gene knock-down and expression analyses. The molecular adjustments that promote maternal investment of honey bee queens in response to their social environment thus reveal a novel mechanism of egg size regulation.

evolutionary biology↗

bioRxiv2022

Structural characterization of a breast cancer-associated mutation in caveolin-1

Caveolin-1 (CAV1) is a membrane sculpting protein that oligomerizes to generate flask-shaped invaginations of the plasma membrane known as caveolae. Mutations in CAV1 have been linked to multiple diseases in humans. Such mutations often interfere with oligomerization and the intracellular trafficking processes required for successful caveolae assembly, but the molecular mechanisms underlying these defects have not been structurally explained. Here, we investigate how a breast cancer-associated mutation in one of the most highly conserved residues in CAV1, P132L, affects CAV1 structure and oligomerization. We show that P132 is positioned at a major site of protomer-protomer interactions within the CAV1 complex, providing a structural explanation for why the mutant protein fails to homo-oligomerize correctly. Using a combination of computational, structural, biochemical, and cell biological approaches, we find that despite its homo-oligomerization defects P132L is capable of forming mixed hetero-oligomeric complexes with wild type CAV1 and that these complexes can be incorporated into caveolae. These findings provide insights into the fundamental mechanisms that control the formation of homo- and hetero-oligomers of caveolins that are essential for caveolae biogenesis, as well as how these processes are disrupted in human disease.

biophysics↗