Sandbox 43: Difference between revisions
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α-lactalbumin is a small protein with calcium ions as cofactors. The binding of the calcium ion increases the stability of the protein in its native conformation and makes the folding of the protein much faster. The binding of the calcium ion acts of a nucleus for the stabilization of the tertiary structure in the protein, without it the process is much slower.<ref>Natalia A. Bushmarina, Clement E. Blanchet, Gregory Vernier, and Vincent Forge. 2006. Cofactor effects on the protein folding reaction: Acceleration of a-lactalbumin refolding by metal ions ''Protein Science'' 15:659–671</ref> In α-lactalbumin native conformation the calcium ion is bound to a unique binding loop.<ref name="ii"> </ref> The calcium binding site is located in the β-domain and is formed by three Asp side chains and two mainchain carbonyls. This site the calcium ion has a pentagonal bypyramidal coordination.<ref name="iv"> </ref> <ref name="iii"> </ref> A secondary calcium binding site involves the residues Thr, Gln, Leu, and Asp. In this site the calcium ion has a tetrahedral coordination.<ref name="iv"> </ref> The <scene name='Sandbox_43/Cal_res/1'>residues</scene> that come into contact with the calcium ion are shown to the right. Protection from thermal, guanidine HCL and urea denaturation is provided by the stability given to the protein from the calcium ion binding. The calcium-binding site has also been shown to weakly bind Mg2+, Na2+, and K+ also. Removal of the calcium ion has shown to induce a conformational change. In the presence of denaturants or absence of calcium ions α-lactalbumin adopts the molten globule state and characterized by the conserved secondary structure but fluctuating tertiary structure.<ref name="ii"> </ref> α-lactalbumin, in its native state, possesses a relatively strong Zn2+ site causing subtle changes in α-lactalbumin structure upon binding to the calcium loaded protein. The Zn2+ is important in the binding of glucose in the lactose synthase complex.<ref name="ii"> </ref> | α-lactalbumin is a small protein with calcium ions as cofactors. The binding of the calcium ion increases the stability of the protein in its native conformation and makes the folding of the protein much faster. The binding of the calcium ion acts of a nucleus for the stabilization of the tertiary structure in the protein, without it the process is much slower.<ref>Natalia A. Bushmarina, Clement E. Blanchet, Gregory Vernier, and Vincent Forge. 2006. Cofactor effects on the protein folding reaction: Acceleration of a-lactalbumin refolding by metal ions ''Protein Science'' 15:659–671</ref> In α-lactalbumin native conformation the calcium ion is bound to a unique binding loop.<ref name="ii"> </ref> The calcium binding site is located in the β-domain and is formed by three Asp side chains and two mainchain carbonyls. This site the calcium ion has a pentagonal bypyramidal coordination.<ref name="iv"> </ref> <ref name="iii"> </ref> A secondary calcium binding site involves the residues Thr, Gln, Leu, and Asp. In this site the calcium ion has a tetrahedral coordination.<ref name="iv"> </ref> The <scene name='Sandbox_43/Cal_res/1'>residues</scene> that come into contact with the calcium ion are shown to the right. Protection from thermal, guanidine HCL and urea denaturation is provided by the stability given to the protein from the calcium ion binding. The calcium-binding site has also been shown to weakly bind Mg2+, Na2+, and K+ also. Removal of the calcium ion has shown to induce a conformational change. In the presence of denaturants or absence of calcium ions α-lactalbumin adopts the molten globule state and characterized by the conserved secondary structure but fluctuating tertiary structure.<ref name="ii"> </ref> α-lactalbumin, in its native state, possesses a relatively strong Zn2+ site causing subtle changes in α-lactalbumin structure upon binding to the calcium loaded protein. The Zn2+ is important in the binding of glucose in the lactose synthase complex.<ref name="ii"> </ref> | ||
=='''Function'''== | |||
α-lactalbumin is found in human milk of mothers who have been lactating for at least one month. It is the most abundant protein providing an osmotic force that drives water from the mothers blood vessels into her mammary glands as well as the formation of lactose as part of the lactose synthesis molecule. It provides much of the nutrients that an infant needs ~15% of the protein and 16% of the nitrogen content.<ref>Jackson JG, Janszenb DB, Lonnerdalc B, Liena EL, Pramuka KP, Kuhlman CF. 2004. A multinational study of α-lactalbumin concentrations in human milk. Journal of Nutritional Biochemistry. 15: 517-521.</ref> | |||
=='''Research'''== | =='''Research'''== | ||
HAMLET (human a-lactalbumin made lethal to tumor cells) is made up of partially unfolded α-lactalbumin and oleic acid. HAMLET has been shown to kill a wide range of tumor cells and embryonal cells but not healthy differentiated cells. It is thought that HAMLET initiate macroautophagy in tumor cells. HAMLET was shown to affect the mitochondria and to cause an apoptotic response with Cytochrome c release, low caspase activation, phosphatidylserine exposure and DNA fragmentation. HAMLET has also been shown to have no adverse effects ''in vivo''. HAMLET translocates to the nuclei, binding to histones and disrupts the function of chromatin in tumor cells<ref>Sonja Aits, Lotta Gustafsson, Oskar Hallgren, Patrick Brest, Mattias Gustafsson, Maria Trulsson, Ann-Kristin Mossberg, Hans-Uwe Simon, Baharia Mograbi and Catharina Svanborg. 2009. HAMLET (human a-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death. ''Int. J. Cancer'' 124, 1008–1019</ref> | HAMLET (human a-lactalbumin made lethal to tumor cells) is made up of partially unfolded α-lactalbumin and oleic acid. HAMLET has been shown to kill a wide range of tumor cells and embryonal cells but not healthy differentiated cells. It is thought that HAMLET initiate macroautophagy in tumor cells. HAMLET was shown to affect the mitochondria and to cause an apoptotic response with Cytochrome c release, low caspase activation, phosphatidylserine exposure and DNA fragmentation. HAMLET has also been shown to have no adverse effects ''in vivo''. HAMLET translocates to the nuclei, binding to histones and disrupts the function of chromatin in tumor cells<ref>Sonja Aits, Lotta Gustafsson, Oskar Hallgren, Patrick Brest, Mattias Gustafsson, Maria Trulsson, Ann-Kristin Mossberg, Hans-Uwe Simon, Baharia Mograbi and Catharina Svanborg. 2009. HAMLET (human a-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death. ''Int. J. Cancer'' 124, 1008–1019</ref> | ||
