Biomedical subjects

Fazly I Ataullakhanov

Publications and source records attributed to Fazly I Ataullakhanov.

4 recordsLinked to original sources

PubMed2005

Force production by disassembling microtubules.

Microtubules (MTs) are important components of the eukaryotic cytoskeleton: they contribute to cell shape and movement, as well as to the motions of organelles including mitotic chromosomes. MTs bind motor enzymes that drive many such movements, but MT dynamics can also contribute to organelle motility. Each MT polymer is a store of chemical energy that can be used to do mechanical work, but how this energy is converted to motility remains unknown. Here we show, by conjugating glass microbeads to tubulin polymers through strong inert linkages, such as biotin-avidin, that depolymerizing MTs exert a brief tug on the beads, as measured with laser tweezers. Analysis of these interactions with a molecular-mechanical model of MT structure and force production shows that a single depolymerizing MT can generate about ten times the force that is developed by a motor enzyme; thus, this mechanism might be the primary driving force for chromosome motion. Because even the simple coupler used here slows MT disassembly, physiological couplers may modulate MT dynamics in vivo.

Animals↗

PubMed2005

A molecular-mechanical model of the microtubule.

Dynamic instability of MTs is thought to be regulated by biochemical transformations within tubulin dimers that are coupled to the hydrolysis of bound GTP. Structural studies of nucleotide-bound tubulin dimers have recently provided a concrete basis for understanding how these transformations may contribute to MT dynamic instability. To analyze these ideas, we have developed a molecular-mechanical model in which structural and biochemical properties of tubulin are used to predict the shape and stability of MTs. From simple and explicit features of tubulin, we define bond energy relationships and explore the impact of their variations on integral MT properties. This modeling provides quantitative predictions about the GTP cap. It specifies important mechanical features underlying MT instability and shows that this property does not require GTP-hydrolysis to alter the strength of tubulin-tubulin bonds. The MT plus end is stabilized by at least two layers of GTP-tubulin subunits, whereas the minus end requires at least one; this and other differences between the ends are explained by asymmetric force balances. Overall, this model provides a new link between the biophysical characteristics of tubulin and the physiological behavior of MTs. It will also be useful in building a more complete description of MT dynamics and mechanics.

Biochemistry↗

PubMed2003

Effect of factor VIII on tissue factor-initiated spatial clot growth.

Using time-lapse videomicroscopy, we studied the role of coagulation factor VIII (fVIII) in tissue factor-initiated spatial clot growth on fibroblast monolayers in a thin layer of non-stirred recalcified plasma from healthy donors or patients with severe Haemophilia A. Analysis of temporal evolution of light-scattering profiles from a growing clot revealed existence of two phases in the clot growth-initiation phase in a narrow (0.2 mm) zone adjacent to activator surface and elongation phase in plasma volume. While the initiation phase did not differ in normal and haemophilic plasmas, the rate of clot growth in the elongation phase in haemophilic plasma constituted only 30% of that in normal plasma. Supplementation of haemophilic plasma with 0.05 U/ml fVIII restored the normal clot growth rate (44.9 +/- 2.5 microm/min) at high but not at low fibroblast density. Our results indicate that the functioning of the intrinsic tenase complex is critical for normal spatial clot growth.

Blood Coagulation↗

PubMed2002

Hemophilia A and B are associated with abnormal spatial dynamics of clot growth.

To gain greater insight into the nature of the bleeding tendency in hemophilia, we compared the spatial dynamics of clotting in platelet-free plasma from healthy donors and from patients with severe hemophilia A or B (factor VIII:C or IX:C<1%). Clotting was initiated via the intrinsic or extrinsic pathway in a thin layer of nonstirred plasma by bringing it in contact with the glass or fibroblast monolayer surface. The results suggest that clot growth is a process consisting of two distinct phases, initiation and elongation. The clotting events on the activator surface and the preceding period free of visible signs of clotting are the initiation phase. In experiments with and without stirring alike, this phase is prolonged in hemophilic plasma activated by the intrinsic, but not the extrinsic pathway. Strikingly, both hemophilia A and B are associated with a significant deterioration in the elongation phase (clot thickening), irrespective of the activation pathway. The rate of clot growth in hemophilic plasma is significantly lower than normal and declines quickly. The resulting clots are thin, which may account for the bleeding disorder.

Blood Coagulation↗