Robert A. Schlegel Professor of Biochemistry and Molecular Biology 428 South Frear, University Park, PA 16802  Phone: (814) 865-6974  Fax: (814) 863-7024  Email: ur3@psu.edu B.S. in chemistry, University of Iowa Ph.D. in biochemistry and molecular biology, Harvard University Schlegel Lab Web Site

A New Subfamily of P-type ATPases Involved in Recognition of Apoptotic Cells

The two leaflets of the plasma membrane bilayer of blood cells differ markedly in composition, with the choline phospholipids, phosphatidylcholine (PC) and sphingomyelin (Sph), concentrated in the outer leaflet and the aminophospholipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE), concentrated in the inner leaflet (Figure 1). Our research is directed at elucidating how this asymmetric transbilayer distribution is established and maintained, and its physiologic function. 

The asymmetric distribution of phospholiids is under the control of two opposing pathways. An aminophospholipid translocase maintains asymmetry by translocating only aminophospholipids from the outer to the inner leaflet; an opposing Ca²⁺-induced pathway (scramblase) permits all the phospholipids to pass from either leaflet to the other, dissipating asymmetry (Figure 1). We have cloned the gene encoding the translocase and it identifies a previously unrecognized subfamily of P-type ATPases with multiple members. Representatives of this new subfamily are found in yeast, nematodes, mammals and plants, and recently, mutations in one of the genes in the subfamily have been identified as responsible for two forms of human inherited cholestasis, or inpaired bile flow. Current research is directed toward elucidating the functions of the other numerous members of the subfamily. 

In lymphocytes and neutrophils undergoing apoptosis, or programmed cell death, the translocase in downregulated and the scramblase upregulated, exposing PS on the cell surface. This surface PS is recognized by macrophages, allowing them to phagocytose apoptotic cells before they can lyse and cause inflammation and tissue damage. Current research is directed toward identifying the receptor on macrophages which recognizes PS, other recognition signals displayed on the surface of apoptotic cells, and the receptors which recognize them. 

 Structural Analysis of Subfamily Type IV (P4) P-type ATPase Transporters

Representative Publications:

• Williamson, P. and R. A. Schlegel. 1994. Back and forth: the regulation and function of transbilayer phospholipid movements in eukaryotic cells (Review). Mol. Memb. Biol. 11:199-216.
• Verhoven, B., R. A. Schlegel, and P. Williamson. 1995. Mechanisms of phosphatidylserine exposure, a phagocytic recognition signal, on apoptotic lymphocytes. J. Exp. Med. 182:1597-1601.
• Tang, X., M. S. Halleck, R. A. Schlegel, and P. Williamson. 1996. A subfamily of P-type ATPases with aminophospholipid transporting activity. Science 272:1495-1497.
• Pradhan, D., S. Krahling, P. Williamson and R. A. Schlegel. 1997. Multiple systems for recognition of apoptotic lymphocytes by macrophages. Mol. Biol. Cell 8:767-778.
• Krahling, S., M. K. Callahan, P. Williamson and R. A. Schlegel.  1999.  Exposure of phosphatidylserine is a general feature in the phagocytosis of apoptotic lymphocytes by macrophages.  Cell Death Diff. 6:183-189.
• Verhoven, B., S. Krahling, R. A. Schlegel and P. Williamson.  1999.  Regulation of phosphatidylserine exposure and phagocytosis of apoptotic T lymphocytes.  Cell Death Differ.  6:262-270.
• Schlegel, R. A., S. Krahling, M. K. Callahan and P. Williamson. 1999. CD14 is a component of multiple recognition systems used by macrophages to phagocytose apoptotic lymphocytes. Cell Death Differ. 6:583-592.
• Halleck, M. S., J. Lawler, S. Blackshaw, L. Gao, P. Nagarajan, C. Hacker, S. Pyle, J. T. Newman, Y.Nakanishi, H. Ando, D. Weinstock, P. Williamson and R. A. Schlegel.  1999.  Differential expression of putative transbilayer amphipath transporters.  Physiol. Genomics 1:139-150.
• Callahan, M. K., P. Williamson and R. A. Schlegel.  2000.  Surface expression of phosphatidylserine on macrophages is required for phagocytosis of apoptotic thymocytes.  Cell Death Differ. 7:645-653.
• Schlegel, R. A., M. K. Callahan and P. Williamson. 2000. The central role of phosphatidylserine in the phagocytosis of apoptotic thymocytes. Ann. N. Y. Acad. Sci. 926:217-225.
• Schlegel, R. A. and P. Williamson. 2001. Phosphatidylserine, a death knell. Cell Death Differ. 8:551-563.
• Williamson, P., A. Christie, T. Kohlin, R. A. Schlegel, P. Comfurius, M. Harmsma, R. F. A. Zwaal and E. M. Bevers. 2001. Phospholipid scramblase activation pathways in lymphocytes. Biochemistry. 40:8065-8072.
• Williamson, P. and R. A. Schlegel. 2002. Transbilayer phospholipid movement and the clearance of apoptotic cells. Biochim. Biophys. Acta 1585:53-63.
• Callahan, M. K., P. M. Popernac, S. Tsutsui, L. Truong, R. A. Schlegel, and A. J. Henderson. 2003. Phosphatidylserine on human immunodeficiency virus envelope is a cofactor for infection of monocytic cells. J. Immunol. 170:4840-4845.
• Callahan, M. K., M. S. Halleck, S. Krahling, A. J. Henderson, P. Williamson, and R. A. Schlegel. 2003. Phosphatidylserine expression and phagocytosis of apoptotic thymocytes during differentiation of monocytic cells. J. Leuk. Biol. 74:846-856. 
• Fan, X., S. Krahling, D. Smith, P. Williamson and R.A. Schlegel. 2004. Macrophage surface expression of annexins I and II in the phagocytosis of apoptotic lymphocytes.  Mol. Biol. Cell 15:2863-2872.
• Williamson, P. and R. A. Schlegel. 2004. Hide and seek: the secret identity of the phosphatidylserine receptor.  J. Biol. 3:14.
• Paterson, J., K. Renkema, L. Burden, M. Halleck, R. A. Schlegel, P. Williamson, and D. L. Daleke. 2006. Lipid specific activation of the murine P4-ATPase Atp8a1 (ATPase II). Biochemistry 45:5367-5376.
• Gekonge, B. N., G. Schiralli, R. A. Schlegel, and A. J. Henderson. 2006. Signal transduction induced by apoptotic cells inhibits HIV transcription in monocytes/macrophages. J. Leukoc. Biol. 80:953-960.
• Zullig, S., L.J. Neukomm, M. Jovanovic, S.J. Charette, N.N. Lyssenko, M.S. Halleck, C.P. Reutelingsperger, R.A. Schlegel and M.O. Hengartner. 2007. Aminophospholipid translocase TAT-1 promotes phosphatidylserine exposure during C. elegans apoptosis. Curr. Biol. 17:994-999.
• Williamson , P., M. S. Halleck, J. Malowitz, S. Ng, X. Fan, S. Krahling, A. T. Remaley, and R. A. Schlegel. 2007. Transbilayer phospholipid movements in ABCA1-deficient cells. PLoS One 2:e729.

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