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Hisactophilin 

A 17kd histidine rich (31 histidine out of 118 aminoacids) actin binding protein from Dictyostelium discoideum (Scheel et al, 1989). The protein is concentrated at the cell cortex, generally coinciding with F-actin.  Probably because of the high histidine content the protein binds to actin in a pH sensitive manner (like cofilin), and undergoes a large pH-dependent change (Houliston et al, 2002).  Hisactophilin induces actin polymerization even in the absence of Mg2+ or K+ at low pH but this effect is less at higher pH within the physiological range. The sequence of hisactophilin bears no obvious sequence homology to any known actin binding protein (Scheel et al, 1989), but the structure is similar to interleukin-1b and the fibroblast growth factor (Habazettl et al, 1992), (as well as certain plant lectins). The structure of hisactophilin is a three-fold symmetrical b-barrel (Habazettl et al, 1992). Two forms of hisactophilin exist (HsI nad HsII), both are myristoylated  and phosphorylatable on threonine and serine (Hanakam et al, 1995). The fact that the protein is membrane associated (Behrisch et al, 1995, Hanakam et al, 1995; Nauman et al, 1996) suggests that the function of hisactophilin is to serve as a link between the cortical actin cytoskeleton and the membrane.  It is surprising therefore that cells in which the hisactophilin is knocked out lack any phenotype, even under conditions designed to stress the cell so that any slight phenotype may be easier to detect (Ponte et al, 2000).  These authors (Ponte et al, 2000) suggest that a phenotype may be found if the cells were grown at low pH as this protein is so pH  sensitive, however Dictyostelium can maintain pHi at about 7.5 in media of a range of pH values so more sophisticated manipulations (Van Duijn & Inouye, 1991) will be required to test this. Another ABP, ponticulin is also likely to function as a major membrane-actin link and so it would be interesting to test for hisactophilin, ponticulin double knockout.

References:-

Behrisch, A., C. Dietrich, et al. (1995). The actin-binding protein hisactophilin binds in vitro to partially charged membranes and mediates actin coupling to membranes. Biochemistry 34, 15182-15190.

Habazettl, J., Gondol, D., Wiltscheck, R., Otlewski, J., Schleicher, M. & Holak, T.A. (1992). "Structure of hisactophilin is similar to interleukin-1b and fibroblast growth factor. Nature, 359, 855-858.

Hammond MS. Houliston RS. & Meiering EM. (1998). "Two-dimensional 1H and 15N NMR titration studies of hisactophilin." Biochemistry & Cell Biology. 76(2-3) 294-301.

Hanakam, F., Eckerskorn, C., Lottspeich, F., Muller-Tabenberger, A., Schafer, W. and Gerisch, G. (1995). "The pH-sensitive actin-binding protein Histactophilin of Dictyostelium exists in two isoforms which both are myristoylated and distributed between plasma membrane and cytoplasm.  J.Biol.Chem. 270, 596-602.

Houliston, R. S., Liu, C., Singh, L. M. R. & Meiering, E. M. (2002) pH and urea dependence of amide hydrogen-deuterium exchange rates in the b-trefoil protein hisactophilin., Biochemistry. 41, 1182-1194.

Ponte, E., Rivero, F., Fechheimer, M., Noegel, A.A., & Bozzaro, S. (2000). "Severe developmental defects in Dictyostelium discoidium null mutants for actin-binding proteins." Mech.Development 91, 153-161.

Nauman, C., Dietrich, C., Behrisch, A., Bayerl, T.M. SChleicher, M., Bucknall, D. & Sackman, E. (1996). "Hisactophilin mediated binding of actin to lip lamellae -  a neutron reflectivity study of protein membrane coupling." Biophys. J. 71, 811-823.

Scheel, J., Ziegelbauer, K., Kupke, T., Humbel, B.M., Noegel, A.A., Gerisch, G. & Schleicher, M. (1989). "Histactophilin, a histidine-rich actin-binding protein from Dictyostelium discoideum. " J.Biol.Chem. 264(5), 2832-2839.

Van Duijn, B. & Inouye, K. (1991). "Regulation of movement speed by intracellular pH during Dictyostelium discoideum chemotaxis." PNAS USA 88, 4951-4955.

Poppenborg L. Friehs K. & Flaschel E. (1997). "The green fluorescent protein is a versatile reporter for bioprocess monitoring." Journal of Biotechnology.  58(2) 79-88.   

Hanakam F. Gerisch G. Lotz S. Alt T. & Seelig A. (1996) "Binding of hisactophilin I and II to lipid membranes is controlled by a pH-dependent myristoyl-histidine switch." Biochemistry. 35(34) 11036-11044.

Stoeckelhuber M. Noegel AA. Eckerskorn C. Kohler J. Rieger D. & Schleicher M. (1996) "Structure/function studies on the pH-dependent actin-binding protein hisactophilin in Dictyostelium mutants. J.Cell Sci. 109(7), 1825-1835

Hanakam F. Albrecht R. Eckerskorn C. Matzner M. & Gerish G. (1996) "Myristoylated and non-myristoylated forms of the pH sensor protein hisactophilin II: Intracellular shuttling to plasma membrane and nucleus monitored in real time by a fusion with green fluorescent protein." EMBO Journal. 15(12), 2935-2943.  

 
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