FAculty directory

Back to alphabetical index

Peter N. Walsh, MD, PhD

Professor Emeritus, Medicine

Professor, Sol Sherry Thrombosis Research Center

Professor, Fels Institute for Cancer Research and Molecular Biology

Professor, Biochemistry

Telephone:  215-707-4375

Fax:  215-707-3005

Email: pnw@temple.edu

Sol Sherry Thrombosis Research Center

Fels Institute of Cancer Research and Molecular Biology

Department of Biochemistry

Amherst College, Amherst, MA

1953-1957, A.B., Pre-Medicine

 

Washington University School of Medicine, St. Louis, MO

1957-1961, M.D., Medicine

 

Barnes Hospital, St. Louis, MO

1961-1962, Medicine Intern

1962-1963, Assistant Resident

 

Washington University School of Medicine, St. Louis, MO

1963-1964, Medicine Fellow (Hematology)

 

Palo Alto-Stanford Hospital, Palo Alto, CA

1964-1965, Senior Resident in Medicine

 

Barnes Hospital, St. Louis, MO

1965-1966, Chief Resident in Medicine

 

Medical Liaison Officer

National Institutes of Health, Bethesda, MD

1966-1969, Urokinase Pulmonary Embolism Trial

 

University of Oxford, Oxford, England

1972, D.Phil., Bio-Med. Sciences

 

Oxford Haemophilia Centre, Churchill Hospital, England

1969-1972, Research Fellow in Blood Coagulation

(NIH Special Postdoctoral Research Fellowship)

 

Return to top

Molecular and Cellular Interactions of Blood Coagulation Proteins.

Research focuses on the characterization, intermolecular interactions and structure-function relationships of coagulation proteins and their interactions with platelets, and includes four specific NIH-funded projects, as follows:

Molecular Interactions of Factor XI. Recent observations resulting in the recognition of the essential role of FXI in hemostasis concern the relationship of its domain structure to its biological function, the molecular genetics of FXI, its molecular and cellular interactions, the elucidation of newly discovered pathways for activation of FXI, and the expression and regulation of its enzymatic activity. The long-term goals of this project are to elucidate the molecular mechanisms involved in the interaction of FXI with protein and cell surface ligands involved in its activation and in the expression and regulation of FXIa enzymatic activity.

Exosite Function in the Catalytic Domain of Coagulation Factor XIa. The long-term goals of this project are to elucidate the molecular mechanisms involved in the interaction of FXIa with its substrate, its cellular (platelet) receptor(s) and its regulators, including the platelet-secreted Kunitz inhibitor, protease nexin-2 and to define the structural biology mediating the exposure of exosites within the catalytic domain that result from the conversion of the zymogen to the protease.

Platelet Receptor-Mediated Factor X Activation. Platelets promote the catalysis FX activation by a complex of FIXa and FVIIIa by a receptor-mediated complex assembled on activated platelets, involving specific, high-affinity, saturable binding sites for FIXa, FVIII and FX, occupancy of which is closely correlated with rates of F-X activation on the platelet surface. The purpose of our studies is to examine the validity of this three-receptor hypothesis and to determine the structural components on the platelet surface and on the enzyme (FIXa) required for the assembly of this important coagulation complex.

Platelet Factor XI. Studies from our laboratory have focused on a novel but poorly understood unique protein, platelet FXI. The objectives of this project are to accomplish a structural and functional characterization of platelet FXI both at the genomic and protein levels, to determine the molecular basis for the presence of platelet FXI in patients with plasma FXI deficiency, to determine the mechanism of association of platelet FXI with the platelet plasma membrane, and to ascertain the mechanisms of its activation and the expression of its enzymatic activity.

Return to top

Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

18441012. Wu W, Sinha D, Shikov S, Yip CK, Walz T, Billings PC, Lear JD, Walsh PN, Factor XI homodimer structure is essential for normal proteolytic activation by factor XIIa, thrombin, and factor XIa. J Biol Chem 283:27(18655-64)2008 Jul 4

18020374. Miller TN, Sinha D, Baird TR, Walsh PN, A catalytic domain exosite (Cys527-Cys542) in factor XIa mediates binding to a site on activated platelets. Biochemistry 46:50(14450-60)2007 Dec 18

17676929. Sinha D, Marcinkiewicz M, Navaneetham D, Walsh PN, Macromolecular substrate-binding exosites on both the heavy and light chains of factor XIa mediate the formation of the Michaelis complex required for factor IX-activation. Biochemistry 46:34(9830-9)2007 Aug 28

17257616. Riley PW, Cheng H, Samuel D, Roder H, Walsh PN, Dimer dissociation and unfolding mechanism of coagulation factor XI apple 4 domain: spectroscopic and mutational analysis. J Mol Biol 367:2(558-73)2007 Mar 23

16752917. London FS, Marcinkiewicz M, Walsh PN, PAR-1-stimulated factor IXa binding to a small platelet subpopulation requires a pronounced and sustained increase of cytoplasmic calcium. Biochemistry 45:23(7289-98)2006 Jun 13

16699514. Papagrigoriou E, McEwan PA, Walsh PN, Emsley J, Crystal structure of the factor XI zymogen reveals a pathway for transactivation. Nat Struct Mol Biol 13:6(557-8)2006 Jun

16229474. Ahmad SS, Walsh PN, Role of the C2 domain of factor VIIIa in the assembly of factor-X activating complex on the platelet membrane. Biochemistry 44:42(13858-65)2005 Oct 25

16085935. Navaneetham D, Jin L, Pandey P, Strickler JE, Babine RE, Abdel-Meguid SS, Walsh PN, Structural and mutational analyses of the molecular interactions between the catalytic domain of factor XIa and the Kunitz protease inhibitor domain of protease nexin 2. J Biol Chem 280:43(36165-75)2005 Oct 28

16042419. Sinha D, Marcinkiewicz M, Lear JD, Walsh PN, Factor XIa dimer in the activation of factor IX. Biochemistry 44:30(10416-22)2005 Aug 2

16042406. Wakabayashi H, Su YC, Ahmad SS, Walsh PN, Fay PJ, A Glu113Ala mutation within a factor VIII Ca2+-binding site enhances cofactor interactions in factor Xase. Biochemistry 44:30(10298-304)2005 Aug 2

15755260. Yang X, Walsh PN, An ordered sequential mechanism for Factor IX and Factor IXa binding to platelet receptors in the assembly of the Factor X-activating complex. Biochem J 390:Pt 1(157-67)2005 Aug 15

15375170. Baglia FA, Shrimpton CN, Emsley J, Kitagawa K, Ruggeri ZM, López JA, Walsh PN, Factor XI interacts with the leucine-rich repeats of glycoprotein Ibalpha on the activated platelet. J Biol Chem 279:47(49323-9)2004 Nov 19

15354267. Walsh PN, Platelet coagulation-protein interactions. Semin Thromb Hemost 30:4(461-71)2004 Aug

15328360. Yang X, Chang YJ, Lin SW, Walsh PN, Identification of residues Asn89, Ile90, and Val107 of the factor IXa second epidermal growth factor domain that are essential for the assembly of the factor X-activating complex on activated platelets. J Biol Chem 279:45(46400-5)2004 Nov 5

15317813. Baglia FA, Gailani D, López JA, Walsh PN, Identification of a binding site for glycoprotein Ibalpha in the Apple 3 domain of factor XI. J Biol Chem 279:44(45470-6)2004 Oct 29

15182201. Sinha D, Badellino KO, Marcinkiewicz M, Walsh PN, Allosteric modification of factor XIa functional activity upon binding to polyanions. Biochemistry 43:23(7593-600)2004 Jun 15

15010476. London FS, Marcinkiewicz M, Walsh PN, A subpopulation of platelets responds to thrombin- or SFLLRN-stimulation with binding sites for factor IXa. J Biol Chem 279:19(19854-9)2004 May 7

14629468. Ahmad SS, London FS, Walsh PN, Binding studies of the enzyme (factor IXa) with the cofactor (factor VIIIa) in the assembly of factor-X activating complex on the activated platelet surface. J Thromb Haemost 1:11(2348-55)2003 Nov

14521588. Walsh PN, Roles of factor XI, platelets and tissue factor-initiated blood coagulation. J Thromb Haemost 1:10(2081-6)2003 Oct

12871539. Ahmad SS, London FS, Walsh PN, The assembly of the factor X-activating complex on activated human platelets. J Thromb Haemost 1:1(48-59)2003 Jan

Return to top