Biology subjects

Sharon, M.

Publications and source records attributed to Sharon, M..

3 recordsLinked to original sources

bioRxiv2018

CSNAP, the smallest CSN subunit, modulates proteostasis through cullin-RING ubiquitin ligases

The cullin-RING ubiquitin E3 ligase (CRL) family consists of ~250 complexes that catalyze ubiquitylation of proteins to achieve cellular regulation. All CRLs are inhibited by the COP9 signalosome complex (CSN) through both enzymatic (deneddylation) and non-enzymatic (steric) mechanisms. The relative contribution of these two mechanisms is unclear. Here, we decouple the mechanisms using CSNAP, the recently discovered ninth subunit of the CSN. We find that CSNAP reduces the affinity of CSN toward CRL complexes. Removing CSNAP does not affect deneddylation, but leads to global effects on the CRL, causing altered reproductive capacity, suppressed DNA damage response, decreased viability, and delayed cell cycle progression. Thus, although CSNAP is only 2% of the CSN mass, it plays a critical role in the steric regulation of CRLs by the CSN.

biochemistry↗

bioRxiv2017

Conformational states during vinculin unlocking differentially regulate focal adhesion properties

Focal adhesions (FAs) are multi-protein complexes that connect the actin cytoskeleton to the extracellular matrix, via integrin receptors. The growth, stability and adhesive functionality of these structures are tightly regulated by mechanical stress, yet, despite the extensive characterization of the integrin adhesome, the mechanisms underlying FA mechanosensitivity are still poorly understood. One of the key candidates for regulating FA-associated mechanosensing is vinculin, a prominent FA component, which was proposed to possess either closed (\"auto-inhibited\") or open (active) conformations. However, a direct demonstration of the nature of conformational transition between the two states is still absent. In this study we combined multiple structural and biological approaches to probe the transition from auto-inhibited to active conformation, and determine its effects on FA structure and dynamics. We further show here that the closed to open transition requires two sequential steps that can differentially regulate FA growth and stability.

biochemistry↗

bioRxiv2017

Role of duplicate genes in determining the tissue-selectivity of hereditary diseases

A longstanding puzzle in human genetics is what limits the clinical manifestation of hundreds of hereditary diseases to certain tissues or cell types, while their causal genes are present and expressed throughout the human body. Here we considered a possible role for paralogs of causal genes in affecting this tissue selectivity. It has been shown across organisms that paralogs can compensate for the loss of each other. We hypothesized that specifically in the disease tissue causal genes and their paralogs are imbalanced, leading to insufficient compensation and to the emergence of disease phenotypes. While demonstrated previously in the context of few specific diseases, this hypothesis was never assessed quantitatively at large-scale. For this, we analyzed functional relationships between causal genes and their paralogs associated with 112 tissue-selective hereditary diseases. To test our hypothesis we used several large-scale omics datasets, including RNA sequencing profiles of over 30 different human tissues. Indeed, the expression of causal genes and their paralogs was significantly imbalanced in their disease tissues compared to unaffected tissues. Imbalanced expression was evident across different disease tissues, and was common to causal genes with single or multiple paralogs. This imbalance was driven by significant upregulation of the causal gene in its disease tissue, often combined with significant down-regulation of a paralog. Nevertheless, in additional 20% of the causal genes, a paralog alone was significantly down-regulated in the disease tissue. Our results suggest that dosage relationships between paralogs affect the phenotypic outcome of germline aberrations, adding paralogs as important modifiers of disease manifestation.

systems biology↗