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Computational models of homologous protein groups are essential in sequence bioinformatics. Due to the diversity and rapid evolution of viruses, the grouping of protein sequences from virus genomes is particularly challenging. The low sequence similarities of homologous genes in viruses require specific approaches for sequence- and structure-based clustering. Furthermore, the annotation of virus genomes in public databases is not as consistent and up to date as for many cellular genomes. To tackle these problems, we have developed VOGDB, which is a database of virus orthologous groups. VOGDB is a multi-layer database that progressively groups viral genes into groups connected by increasingly remote similarity. The first layer is based on pair-wise sequence similarities, the second layer is based on the sequence profile alignments, and the third layer uses predicted protein structures to find the most remote similarity. VOGDB groups allow for more sensitive homology searches of novel genes and increase the chance of predicting annotations or inferring phylogeny. VOGD B uses all virus genomes from RefSeq and partially reannotates them. VOGDB is updated with every RefSeq release. The unique feature of VOGDB is the inclusion of both prokaryotic and eukaryotic viruses in the same clustering process, which makes it possible to explore old evolutionary relationships of the two groups. VOGDB is freely available at vogdb.org under the CC BY 4.0 license. [ABSTRACT FROM AUTHOR]

Photoacoustic and absorption spectroscopy imaging are safe and non-invasive molecular quantification techniques, which do not utilize ionizing radiation and allow for repeated probing of samples without them being contaminated or damaged. Here we assessed the potential of these techniques for measuring biochemical parameters. We investigated the statistical association between 31 time and frequency domain features derived from photoacoustic and absorption spectroscopy signals and 19 biochemical blood parameters. We found that photoacoustic and absorption spectroscopy imaging features are significantly correlated with 14 and 17 individual biochemical parameters, respectively. Moreover, some of the biochemical blood parameters can be accurately predicted based on photoacoustic and absorption spectroscopy imaging features by polynomial regression. In particular, the levels of uric acid and albumin can be accurately explained by a combination of photoacoustic and absorption spectroscopy imaging features (adjusted R-squared > 0.75), while creatinine levels can be accurately explained by the features of the photoacoustic system (adjusted R-squared > 0.80). We identified a number of imaging features that inform on the biochemical blood parameters and can be potentially useful in clinical diagnosis. We also demonstrated that linear and non-linear combinations of photoacoustic and absorption spectroscopy imaging features can accurately predict some of the biochemical blood parameters. These results demonstrate that photoacoustic and absorption spectroscopy imaging systems show promise for future applications in clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Hearing loss is the most common sensory impairment in humans. Globally, GJB2 is the most common responsible gene, with missense variants being the most frequent variant type. Pathogenic missense variants in the GJB2 gene cause isolated hearing loss and hearing loss combined with skin diseases. However, the mechanism by which different missense variants cause different hearing loss phenotypes is unknown. We have summarized 84 functionally studied missense variants and reviewed the clinical phenotypes and the molecular mechanisms that affected connexon and gap junction functions. We have also compiled a comprehensive dataset of GJB2 missense variants from public databases and published literature and found that over 2/3 of the GJB2 missense variants are currently classified as variants of uncertain significance. With the development of cutting-edge deep mutational scanning technology, we predict that the molecular mechanisms by which all missense variants of GJB2 lead to different clinical phenotypes will be elucidated. These gained insights will facilitate the use of genetic testing in the prevention and control of hearing loss. The GJB2 gene is the most common gene responsible for hearing loss (HL) worldwide, and missense variants are the most abundant type. GJB2 pathogenic missense variants cause nonsyndromic HL (autosomal recessive and dominant) and syndromic HL combined with skin diseases. However, the mechanism by which these different missense variants cause the different phenotypes is unknown. Over 2/3 of the GJB2 missense variants have yet to be functionally studied and are currently classified as variants of uncertain significance (VUS). Based on these functionally determined missense variants, we reviewed the clinical phenotypes and investigated the molecular mechanisms that affected hemichannel and gap junction functions, including connexin biosynthesis, trafficking, oligomerization into connexons, permeability, and interactions between other coexpressed connexins. We predict that all possible GJB2 missense variants will be described in the future by deep mutational scanning technology and optimizing computational models. Therefore, the mechanisms by which different missense variants cause different phenotypes will be fully elucidated. [ABSTRACT FROM AUTHOR]

One‐third of the human proteome is comprised of membrane proteins, which are particularly vulnerable to misfolding and often require folding assistance by molecular chaperones. Calnexin (CNX), which engages client proteins via its sugar‐binding lectin domain, is one of the most abundant ER chaperones, and plays an important role in membrane protein biogenesis. Based on mass spectrometric analyses, we here show that calnexin interacts with a large number of nonglycosylated membrane proteins, indicative of additional nonlectin binding modes. We find that calnexin preferentially bind misfolded membrane proteins and that it uses its single transmembrane domain (TMD) for client recognition. Combining experimental and computational approaches, we systematically dissect signatures for intramembrane client recognition by calnexin, and identify sequence motifs within the calnexin TMD region that mediate client binding. Building on this, we show that intramembrane client binding potentiates the chaperone functions of calnexin. Together, these data reveal a widespread role of calnexin client recognition in the lipid bilayer, which synergizes with its established lectin‐based substrate binding. Molecular chaperones thus can combine different interaction modes to support the biogenesis of the diverse eukaryotic membrane proteome. Synopsis: Calnexin is a membrane‐integral chaperone that acts on glycosylated proteins. This study shows that its transmembrane domain is also involved in substrate binding, defines how intramembrane substrate recognition occurs, and reveals that this additional binding mode supports chaperoning. The mass‐spectrometric interactome of calnexin contains many non‐glycosylated membrane proteins.Calnexin can bind membrane protein substrates in the lipid bilayer via its own transmembrane domain.A systematic analysis reveals how calnexin recognizes particular features within its clients in the membrane.Intra‐membrane client recognition synergizes with sugar‐based recognition of calnexin clients to protect labile chaperone substrates. [ABSTRACT FROM AUTHOR]

Human endogenous retrovirus (HERVs), normally silenced by methylation or mutations, can be reactivated by multiple environmental factors, including infections with exogenous viruses. In this work, we investigated the transcriptional activity of HERVs in human A549 cells infected by two wild-type (PR8M, SC35M) and one mutated (SC35MΔNS1) strains of Influenza A virus (IAVs). We found that the majority of differentially expressed HERVs (DEHERVS) and genes (DEGs) were up-regulated in the infected cells, with the most significantly enriched biological processes associated with the genes differentially expressed exclusively in SC35MΔNS1 being linked to the immune system. Most DEHERVs in PR8M and SC35M are mammalian apparent LTR retrotransposons, while in SC35MΔNS1, more HERV loci from the HERVW9 group were differentially expressed. Furthermore, up-regulated pairs of HERVs and genes in close chromosomal proximity to each other tended to be associated with immune responses, which implies that specific HERV groups might have the potential to trigger specific gene networks and influence host immunological pathways. [ABSTRACT FROM AUTHOR]

Author(s): Marc Strous [1]; Eric Pelletier [2]; Sophie Mangenot [2]; Thomas Rattei [3]; Angelika Lehner [4, 5]; Michael W. Taylor [4]; Matthias Horn [4]; Holger Daims [4]; Delphine Bartol-Mavel [2]; [...]

The Escherichia coli chaperonin GroEL and its cofactor GroES promote protein folding by sequestering nonnative polypeptides in a cage like structure. The contribution of this system to protein folding across the entire E. coli proteome is defined.

Author(s): James E. Galagan (corresponding author) [1]; Sarah E. Calvo [1]; Katherine A. Borkovich [2]; Eric U. Selker [3]; Nick D. Read [4]; David Jaffe [1]; William FitzHugh [5]; Li-Jun [...]

Author(s): Andreas Ruepp [1]; Werner Graml [1]; Martha-Leticia Santos-Martinez [1]; Kristin K. Koretke [2]; Craig Volker [2]; H. Werner Mewes [3]; Dmitrij Frishman [3]; Susanne Stocker [3]; Andrei N. Lupas [...]