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Myofibrillar myopathy (MFM) is a human disease that is characterized by focal myofibrillar destruction and pathological cytoplasmic protein aggregations. In an extended German pedigree with a novel form of MFM characterized by clinical features of a limb-girdle myopathy and morphological features of MFM, we identified a cosegregating, heterozygous nonsense mutation (8130G -> A; W2710X) in the filamin c gene ( FLNC) on chromosome 7q32.1. The mutation is the first found in FLNC and is localized in the dimerization domain of filamin c. Functional studies showed that, in the truncated mutant protein, this domain has a disturbed secondary structure that leads to the inability to dimerize properly. As a consequence of this malfunction, the muscle fibers of our patients display massive cytoplasmic aggregates containing filamin c and several Z-disk-associated and sarcolemmal proteins
Partikelverstärkte Oberflächenplasmonresonanz für die Quantifizierung von Matrix Metalloproteinase-2
(2004)
Previous work has shown that mutations in muscle LIM protein (MLP) can cause hypertrophic cardiomyopathy (HCM). In order to gain an insight into the molecular basis of the disease phenotype, we analysed the binding characteristics of wild-type MLP and of the (C58G) mutant MLP that causes hypertrophic cardiomyopathy. We show that MLP can form a ternary complex with two of its previously documented myofibrillar ligand proteins, N-RAP and alpha-actinin, which indicates the presence of distinct, non-overlapping binding sites. Our data also show that, in comparison to wild-type MLP, the capacity of the mutated MLP protein to bind both N-RAP and alpha-actinin is significantly decreased. In addition, this single point mutation prevents zinc coordination and proper folding of the second zinc-finger in the first LIM domain, which consequently renders the protein less stable and more susceptible to proteolysis. The molecular basis for HCM-causing mutations in the MLP gene might therefore be an alteration in the equilibrium of interactions of the ternary complex MLP-N-RAP-alpha-actinin. This assumption is supported by the previous observation that in the pathological situation accompanied by MLP down regulation, cardiomyocytes try to compensate for the decreased stability of MLP protein by increasing the expression of its ligand N-RAP, which might finally result in the development of myocyte disarray that is characteristic of this disease
Detection of subicomolar concentrations of human matrix metalloproteinase-2 by an optical biosensor
(2004)
We describe in this paper the development of a one-step sandwich assay for the highly sensitive and fast detection of human matrix metalloproteinase (MMP)-2 (EC 3.4.24.24), using surface plasmon resonance (SPR). For the assay, two ligands were selected: monoclonal anti-MMP-2 antibody Ab-2 and the tissue inhibitor of metalloproteinases (TIMP)-2. They were chosen on the basis of (1) their affinities to MMP-2, (2) the efficiency of immobilization to the sensor chip, (3) the efficiency of adsorption to colloidal gold, and (4) the stability of these protein-coated gold particles. The assay included mixing of MMP-2 with antibody Ab-2 adsorbed to colloidal gold with a diameter of about 20 rim and injection into the flowcell of the SPR instrument containing immobilized TIMP-2. By using colloidal gold particles an amplification factor of 114 and a detection limit of 0.5 pM for MMP-2 were obtained. The precision of the assay was high even at low analyte concentrations, the standard deviation being 8.3% for five determinations of 1 pM MMP- 2. No significant binding was observed with the structurally related MMP-9. The assay is far more sensitive and faster than commonly used methods for MMP-2 detection. As TIMP-bound MMP-2 is not detected by this method, the assay can be applied for measuring free MMP-2, reflecting the imbalance of free and inhibitor-bound enzyme in various pathological situations. (C) 2004 Elsevier Inc. All rights reserved
Xin is a protein that is expressed during early developmental stages of cardiac and skeletal muscles. Immunolocalization studies indicated a peripheral localization in embryonic mouse heart, where Xin localizes with beta- catenin and N-cadherin. In adult tissues, Xin is found primarily in the intercalated discs of cardiomyocytes and the myotendinous junctions of skeletal muscle cells, both specialized attachment sites of the myofibrillar ends to the sarcolemma. A large part of the Xin protein consists of unique 16 amino acid repeats with unknown function. We have investigated the characteristics of the Xin repeats by transfection experiments and actin-binding assays and ascertained that, upon expression in cultured cells, these repeats bind to and stabilize the actin-based cytoskeleton. In vitro co- sedimentation assays with skeletal muscle actin indicated that they not only directly bind actin filaments, but also have the capability of arranging microfilaments into networks that sediment upon low-speed centrifugation. Very similar repeats were also found in Xin-repeat protein 2' (XIRP2), a novel protein that seems to be expressed mainly in striated muscles. Human XIRP2 contains 28 Xin repeats with properties identical to those of Xin. We conclude that the Xin repeats define a novel, repetitive actin-binding motif present in at least two different muscle proteins. These Xin- repeat proteins therefore constitute the first two members of a novel family of actin-binding proteins
Integration of titin into the sarcomeres of cultured differentiating human skeletal muscle cells
(1996)
Assignment of the human gene for the sarcomeric M-band protein myomesin (MYOM1) to 18p11.31-p11.32
(1998)
Chromosomal assignment of the human gene for endosarcomeric cytoskeletal M-protein (MYOM2) to 8p23.3
(1999)
Filamin c is the predominantly expressed filamin isoform in striated muscles. It is localized in myofibrillar Z- discs, where it binds FATZ and myotilin, and in myotendinous junctions and intercalated discs. Here, we identify Xin, the protein encoded by the human gene 'cardiomyopathy associated 1' (CMYA1) as filamin c binding partner at these specialized structures where the ends of myofibrils are attached to the sarcolemma. Xin directly binds the EVH1 domain proteins Mena and VASP. In the adult heart, Xin and Mena/VASP colocalize with filamin c in intercalated discs. In cultured cardiomyocytes, the proteins also localize in the nonstriated part of myofibrils, where sarcomeres are assembled and an extensive reorganization of the actin cytoskeleton occurs. Unusual intraexonic splicing events result in the existence of three Xin isoforms that associate differentially with its ligands. The identification of the complex filamin c-Xin-Mena/VASP provides a first glance on the role of Xin in the molecular mechanisms involved in developmental and adaptive remodeling of the actin cytoskeleton during cardiac morphogenesis and sarcomere assembly. (c) 2006 Elsevier Inc. All rights reserved
Hypervelocity stars are rare objects, mostly main-sequence (MS) B stars, traveling so fast that they will eventually escape from the Milky Way. Recently, it has been shown that the popular Hills mechanism, in which a binary system is disrupted via a close encounter with the supermassive black hole at the Galactic center, may not be their only ejection mechanism. The analyses of Gaia data ruled out a Galactic center origin for some of them, and instead indicated that they are extreme disk runaway stars ejected at velocities exceeding the predicted limits of classical scenarios (dynamical ejection from star clusters or binary supernova ejection). We present the discovery of a new extreme disk runaway star, PG 1610+062, which is a slowly pulsating B star bright enough to be studied in detail. A quantitative analysis of spectra taken with ESI at the Keck Observatory revealed that PG 1610+062 is a late B-type MS star of 4–5 M⊙ with low projected rotational velocity. Abundances (C, N, O, Ne, Mg, Al, Si, S, Ar, and Fe) were derived differentially with respect to the normal B star HD 137366 and indicate that PG 1610+062 is somewhat metal rich. A kinematic analysis, based on our spectrophotometric distance (17.3 kpc) and on proper motions from Gaia’s second data release, shows that PG 1610+062 was probably ejected from the Carina-Sagittarius spiral arm at a velocity of 550 ± 40 km s−1, which is beyond the classical limits. Accordingly, the star is in the top five of the most extreme MS disk runaway stars and is only the second among the five for which the chemical composition is known.
Aims. To gain a realistic picture of the donor star in Vela X-1, we constructed a hydrodynamically consistent atmosphere model describing the wind stratification while properly reproducing the observed donor spectrum. To investigate how X-ray illumination affects the stellar wind, we calculated additional models for different X-ray luminosity regimes. Methods. We used the recently updated version of the Potsdam Wolf-Rayet code to consistently solve the hydrodynamic equation together with the statistical equations and the radiative transfer. Results. The wind flow in Vela X-1 is driven by ions from various elements, with Fe III and S III leading in the outer wind. The model-predicted mass-loss rate is in line with earlier empirical studies. The mass-loss rate is almost unaffected by the presence of the accreting NS in the wind. The terminal wind velocity is confirmed at u(infinity) approximate to 600 km s(-1). On the other hand, the wind velocity in the inner region where the NS is located is only approximate to 100 km s(-1), which is not expected on the basis of a standard beta-velocity law. In models with an enhanced level of X-rays, the velocity field in the outer wind can be altered. If the X-ray flux is too high, the acceleration breaks down because the ionization increases. Conclusions. Accounting for radiation hydrodynamics, our Vela X-1 donor atmosphere model reveals a low wind speed at the NS location, and it provides quantitative information on wind driving in this important HMXB.
Based on new Chandra X-ray telescope data, we present empirical evidence of plasma Compton cooling during a flare in the non-pulsating massive X-ray binary 4U1700-37. This behaviour might be explained by quasi-spherical accretion on to a slowly rotating magnetized neutron star (NS). In quiescence, the NS in 4U1700-37 is surrounded by a hot radiatively cooling shell. Its presence is supported by the detection of mHz quasi-periodic oscillations likely produced by its convection cells. The high plasma temperature and the relatively low X-ray luminosity observed during the quiescence, point to a small emitting area similar to 1 km, compatible with a hotspot on an NS surface. The sudden transition from a radiative to a significantly more efficient Compton cooling regime triggers an episode of enhanced accretion resulting in a flare. During the flare, the plasma temperature drops quickly. The predicted luminosity for such transitions, similar to 3 x 10(35) erg s(-1), is very close to the luminosity of 4U1700-37 during quiescence. The transition may be caused by the accretion of a clump in the stellar wind of the donor star. Thus, a magnetized NS nature of the compact object is strongly favoured.
Based on our new NuSTAR X-ray telescope data, we rule out any cyclotron line up to 60 keV in the spectra of the high-mass X-ray binary 4U2206+54. In particular, we do not find any evidence of the previously claimed line around 30 keV, independently of the source flux, along the spin pulse. The spin period has increased significantly, since the last observation, up to 5750 +/- 10 s, confirming the rapid spin-down rate (nu)over dot = -1.8 x 10(-14) Hz s(-1). This behaviour might be explained by the presence of a strongly magnetized neutron star (B-s > several times 10(13) G) accreting from the slow wind of its main-sequence O9.5 companion.
Context. X-ray radiation from accreting compact objects is an important part of stellar feedback. The metal-poor galaxy ESO 338-4 has experienced vigorous starburst during the last <40 Myr and contains some of the most massive super star clusters in the nearby Universe. Given its starburst age and its star-formation rate, ESO 338-4 is one of the most efficient nearby manufactures of neutron stars and black holes, hence providing an excellent laboratory for feedback studies. Aims. We aim to use X-ray observations with the largest modern X-ray telescopes XMM-Newton and Chandra to unveil the most luminous accreting neutron stars and black holes in ESO 338-4. Methods. We compared X-ray images and spectra with integral field spectroscopic observations in the optical to constrain the nature of strong X-ray emitters. Results. X-ray observations uncover three ultraluminous X-ray sources (ULXs) in ESO 338-4. The brightest among them, ESO 338 X-1, has X-ray luminosity in excess of 10(40) erg s(-1). We speculate that ESO 338-4 X-1 is powered by accretion on an intermediate-mass (greater than or similar to 300 M-circle dot)black hole. We show that X-ray radiation from ULXs and hot superbubbles strongly contributes to He II ionization and general stellar feedback in this template starburst galaxy.