Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous experimental work has shown that the functional properties of the mechanosensitive channel of large conductance (MscL) are affected by variations in lipid composition. Here, we utilize molecular dynamics simulations of Mycobacterium tuberculosis MscL to investigate such lipid composition effects on a molecular level. In particular, two sets of simulations were performed. In the first, trajectories using lipids with different headgroups (phosphatidylcholine and phosphatidylethanolamine) were compared. Protein-lipid interactions were clearly altered by the headgroup changes, leading to conformational differences in the C-terminal region of M. tuberculosis MscL. In the second set of simulations, lipid tails were gradually shortened, thinning the membrane over a molecular dynamics trajectory. These simulations showed evidence of hydrophobic matching between MscL and the lipid membrane, as previously proposed. For all simulations, protein-lipid interaction energies in the second transmembrane region were correlated to mutagenic data, emphasizing the importance of lipid interactions for proper MscL function.
 ...
PMID:Investigating lipid composition effects on the mechanosensitive channel of large conductance (MscL) using molecular dynamics simulations. 1294 69

A 28-year-old woman with polycystic ovarian syndrome (PCOS) had attempted four assisted conception treatments, all of which were complicated by lack of response of the endometrium to the hypo-oestrogenic state induced with gonadotrophin releasing hormone analogue (GnRHa). Consequently, two treatment cycles were abandoned, one prior to the ovulation induction of a fresh IVF treatment and the other prior to oestrogen replacement for a frozen-thawed embryo transfer treatment cycle. Extended down-regulation eventually resulted in endometrial thinning and allowed completion of the other two treatments, but the outcome was negative. A targeted mid-cycle ultrasound scan in a natural cycle at follow-up showed thick, non-homogenous endometrium. A repeat hysteroscopy on this occasion showed abnormal endometrium with chalk-like deposits. Histological diagnosis was chronic endometritis and endometrial hyperplasia with focal atypia. Microbiological tests, including those for Mycobacterium tuberculosis, were negative. Because of atypical endometrial hyperplasia, this patient is currently under close follow-up by the original referring team. This case highlights inherent endometrial pathology presenting as non-responding endometrium to hormonal down-regulation, the limitations of conventional ultrasound scans, and the complimentary role of concomitant hysteroscopy in the correct identification of endometrial lesions that may negatively affect the assisted conception treatments.
 ...
PMID:Unusual presentation of a woman with polycystic ovaries and complex endometrial pathology. 1645 32

The prokaryotic mechanosensitive channel of large conductance (MscL) is a remarkable integral membrane protein. During hypo-osmotic shock, it responses to membrane tension through large conformational changes, that lead to an open state of the pore. The structure of the channel from Mycobacterium tuberculosis has been resolved in the closed state. Numerous experiments have attempted to trap the channel in its open state but they did not succeed in obtaining a structure. A gating mechanism has been proposed based on different experimental data but there is no experimental technique available to follow this process in atomic details. In addition, it has been shown that a decrease of the lipid bilayer thickness lowered MscL activation energy and stabilized a structurally distinct closed channel intermediate. Here, we use atomistic molecular dynamics simulations to investigate the effect of the lipid bilayer thinning on our model of the structure of the Escherichia coli. We thoroughly analyze simulations of the channel embedded in two pre-equilibrated membranes differing by their hydrophobic tail length (DMPE and POPE). The MscL structure remains stable in POPE, whereas a distinct structural state is obtained in DMPE in response to hydrophobic mismatch. This latter is obtained by tilts and kinks of the transmembrane helices, leading to a widening and a diminution of the channel height. Part of these motions is guided by a competition between solvent and lipids for the interaction with the periplasmic loops. We finally conduct a principal component analysis of the simulation and compare anharmonic motions with harmonic ones, previously obtained from a coarse-grained normal mode analysis performed on the same structural model. Significant similarities exist between low-frequency harmonic motions and those observed with essential dynamics in DMPE. In summary, change in membrane thickness permits to accelerate the conformational changes involved in the mechanics of the E. coli channel, providing a closed structural intermediate en route to the open state. These results give clues for better understanding why the channel activation energy is lowered in a thinner membrane.
 ...
PMID:New insights of membrane environment effects on MscL channel mechanics from theoretical approaches. 1800 82

This study aims to explore gating mechanisms of mechanosensitive channels in terms of membrane tension, membrane adaptation, protein conformation, and energetics. The large conductance mechanosensitive channel from Mycobacterium tuberculosis (Tb-MscL) is used as a model system; Tb-MscL acts as a safety valve by releasing small osmolytes through the channel opening under extreme hypoosmotic conditions. Based on the assumption that the channel gating involves tilting of the transmembrane (TM) helices, we have performed free energy simulations of Tb-MscL as a function of TM helix tilt angle in a dimyristoylphosphatidylcholine bilayer. Based on the change in system dimensions, TM helix tilting is shown to be essentially equivalent to applying an excess surface tension to the membrane, causing channel expansion, lipid adaptation, and membrane thinning. Such equivalence is further corroborated by the observation that the free energy cost of Tb-MscL channel expansion is comparable to the work done by the excess surface tension. Tb-MscL TM helix tilting results in an expanded water-conducting channel of an outer dimension similar to the proposed fully open MscL structure. The free energy decomposition indicates a possible expansion mechanism in which tilting and expanding of TM2 facilitates the iris-like motion of TM1, producing an expanded Tb-MscL.
 ...
PMID:Membrane tension, lipid adaptation, conformational changes, and energetics in MscL gating. 2180 35

Mycolactone is a diffusible lipid secreted by the human pathogen Mycobacterium ulcerans, which induces the formation of open skin lesions referred to as Buruli ulcers. Here, we show that mycolactone operates by hijacking the Wiskott-Aldrich syndrome protein (WASP) family of actin-nucleating factors. By disrupting WASP autoinhibition, mycolactone leads to uncontrolled activation of ARP2/3-mediated assembly of actin in the cytoplasm. In epithelial cells, mycolactone-induced stimulation of ARP2/3 concentrated in the perinuclear region, resulting in defective cell adhesion and directional migration. In vivo injection of mycolactone into mouse ears consistently altered the junctional organization and stratification of keratinocytes, leading to epidermal thinning, followed by rupture. This degradation process was efficiently suppressed by coadministration of the N-WASP inhibitor wiskostatin. These results elucidate the molecular basis of mycolactone activity and provide a mechanism for Buruli ulcer pathogenesis. Our findings should allow for the rationale design of competitive inhibitors of mycolactone binding to N-WASP, with anti-Buruli ulcer therapeutic potential.
 ...
PMID:Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation. 2354 80

The incidence of infection by Mycobacterium marinum is rising, mainly due to the increasing popularity of home aquariums. The infection typically manifests as skin lesions, with septic arthritis being a rare presentation form. The disease is difficult to diagnose even when there is a high clinical suspicion, as culture in specific media may not yield positive findings. Thus, establishment of appropriate treatment is often delayed. Synovectomy, capsular thinning, and joint drainage together with prolonged, combined antibiotic therapy may be needed to cure the infection.
...
PMID:Septic arthritis caused by Mycobacterium marinum. 2651 31