Navigation

Researchers at UCD

researcher

Margaret Worrall

Senior Lecturer

School Of Biomolecular & Biomed Science
Conway Institute
Belfield
Dublin 4

Tel: +353 1 7166779
Email: mworrall@ucd.ie

Publications

 

Book Chapters

McGettrick, AF and Worrall, DM; (2004) 'Dye-ligand affinity chromatography' In: Paul Cutler (eds). Methods in Molecular Biology 244: Protein purification protocols. Totowa, New Jersey, USA: Humana Press Inc. , pp.151-157 [Details]
McGettrick, AF and Worrall, DM; (2004) 'Extraction of recombinant protein from bacteria' In: Paul Cutler (eds). Methods in Molecular Biology 244: Protein Purification Protocols. Totowa, New Jersey: Humana Press Inc. , pp.29-35 [Details]
 

Peer Reviewed Journals

Anguissola, S,McCormack, WJ,Morrin, MA,Higgins, WJ,Fox, DM,Worrall, DM (2011) 'Pigment Epithelium-Derived Factor (PEDF) Interacts with Transportin SR2, and Active Nuclear Import Is Facilitated by a Novel Nuclear Localization Motif'. PLoS ONE, 6 . [DOI] [Details]
de Koning, PJA,Kummer, JA,de Poot, SAH,Quadir, R,Broekhuizen, R,McGettrick, AF,Higgins, WJ,Devreese, B,Worrall, DM,Bovenschen, N; (2011) 'Intracellular Serine Protease Inhibitor SERPINB4 Inhibits Granzyme M-Induced Cell Death'. PLoS ONE, 6 . [DOI] [Details]
Anguissola S, McCormack WJ, Morrin MA, Higgins WJ, Fox DM, Worrall DM; (2011) 'Pigment Epithelium-Derived Factor (PEDF) Interacts with Transportin SR2, and Active Nuclear Import Is Facilitated by a Novel Nuclear Localization Motif'. PLoS ONE, 6 (10). [Details]
Higgins WJ, Fox DM, Kowalski PS, Nielsen JE, Worrall DM; (2010) 'Heparin enhances serpin inhibition of the cysteine protease cathepsin L'. Journal of Biological Chemistry, 285 (6):3722-3729. [DOI] [Details]
Law RH, Irving JA, Buckle AM, Ruzyla K, Buzza M, Bashtannyk-Puhalovich TA, Beddoe TC, Nguyen K, Worrall DM, Bottomley SP, Bird PI, Rossjohn J, Whisstock JC; (2005) 'The high resolution crystal structure of the human tumor suppressor maspin reveals a novel conformational switch in the G-helix'. Journal of Biological Chemistry, 280 (23):22356-22364. [Details]
Aghajanian S, Worrall DM; (2002) 'Identification and characterization of the gene encoding the human phosphopantetheine adenylyltransferase and dephospho-CoA kinase bifunctional enzyme (CoA synthase). '. Biochemical Journal, 365 (1):13-18. [Details]
Irving JA, Pike RN, Dai W, Bromme D, Worrall DM, Silverman GA, Coetzer TH, Dennison C, Bottomley SP, Whisstock JC. ; (2002) 'Evidence that serpin architecture intrinsically supports papain-like cysteine protease inhibition: engineering alpha(1)-antitrypsin to inhibit cathepsin proteases. '. Biochemistry, 41 (15):4998-5004. [Details]
Blacque OE, Worrall DM; (2002) 'Evidence for a direct interaction between the tumor suppressor serpin, maspin, and types I and III collagen. '. Journal of Biological Chemistry, 277 (13):10783-10788. [Details]
McGettrick AF, Barnes RC, Worrall DM.; (2001) 'SCCA2 inhibits TNF-mediated apoptosis in transfected HeLa cells. The reactive centre loop sequence is essential for this function and TNF-induced cathepsin G is a candidate target. '. European Journal of Biochemistry, 286 (22):5868-5875. [Details]
Mansell A, Reinicke A, Worrall DM, & ONeill LA.; (2001) 'The serine protease inhibitor antithrombin III inhibits LPS-mediated NF-kappaB activation by TLR-4'. FEBS Letters, 508 :313-317. [Details]
Barnes, R., Coulter, J.C. and Worrall, D.M.; (2000) 'Immunoreactivity of recombinant SCCA and leupin/SCCA-2 : implications for tumor marker detection'. Gynecologic Oncology, 78 :62-66. [Details]
Coulter, J., Barnes, R.C. and Worrall, D.M.; (1998) 'Expression of the serpins SCCA and leupin in normal and malignant squamous epithelium of the cervix'. British Journal of Cancer, 78 . [Details]
McCarthy, B.J. and Worrall, D.M.; (1997) 'Analysis of serpin inhibitory function by mutagenesis of ovalbumin and generation of chimeric ovalbumin / PAI-2 fusion proteins'. Journal of Molecular Biology, 267 :561-569. [Details]
Barnes, R.C. and Worrall, D.M; (1995) 'Identification of a novel human serpin gene; isolation, sequencing and expression of leupin'. FEBS Letters, 373 :61-65. [Details]

Other Journals

Bird PI, Pak SC, Worrall DM, Bottomley SP.; (2004) 'Production of recombinant serpins in Escherichia coli' Methods 32 (2) :169-176. [Details]
                                                                                           

Research

Research Interests

Our research is primarily focused on the serpin (serine protease inhibitor) superfamily of proteins and the role of particular serpins in cancer. Serpins are involved in a wide range of physiological processes including coagulation, inflammation and cell migration. There are 35 human serpins and most regulate proteases through a suicide inhibition mechanism, which has been elucidated using the archetypal plasma serpin, a1-antitrypsin. However some serpin gene products lack the ability to inhibit proteases and have other functions such as hormone transport, tumour suppression or growth factor activity. These have been coined non-inhibitory serpins and include PEDF (pigment epithelial derived factor), maspin (mammary serpin) and thyroxine binding globulin.

We are interested in PEDF and maspin since both of these serpins have therapeutic potential as inhibitors of angiogenesis. PEDF is of particular importance in the eye and may be useful for treating diabetic retinopathy and age-related macular degeneration. Maspin is known to have tumour suppressor properties in breast and prostate. The mechanism of these serpins is not well elucidated, and although they can exert their function as exogenous proteins added to cellular assays, there is also evidence that they are found in significant amounts intracellularly and in the nucleus.

We have carried out yeast-2-hybrid studies to identify target proteins for both maspin and PEDF in order to gain a greater insight into their mechanism of action. In the case of maspin, we have shown binding with collagen types 1 and 3, which may facilitate cell adhesion in the extracellular matrix. For PEDF, we have identified an interaction with the nuclear transport protein transportin-SR2 and we have found that PEDF is actively transported to the nucleus. We have also identified a novel nuclear localisation signal sequence common to PEDF and other transportin substrates and following mutagenesis of this motif PEDF is excluded from the nucleus.

The nuclear uptake of PEDF may be critical for its function as an antiangiogenic factor and this is currently being assessed using a mutagenesis approach. Little is known about cellular trafficking of maspin or the mechanism of maspin tumour suppression, and we are also investigating maspin localisation, structure and function.

A further focus of the research group is to characterise two orphan human A-clade serpins, which we have identified on chromosome 14. Expression studies show that both are made in the liver and are likely to be present in human plasma, but their function has yet to be elucidated. Using purified recombinant proteins, we are investigating conformational stability and inhibitory profiles of these proteins

Research projects currently ongoing:

Cellular uptake and nuclear localisation of PEDF: importance of phosphorylation and relevance to anti-angiogenic and neurotrophic function.
Investigation into a novel nuclear localisation signal sequence for transportin cargo proteins.
Cellular localisation of the related non-inhibitory serpin, maspin and isolation of a putative maspin receptor.
Structure-function studies on maspin (in collaboration with Dr J. Whisstock, Monash University)
Characterisation of the orphan human A-clade serpins

 

     

Collaborators

Internal Collaborators

  • Dr. Carmel Hensey
  • Dr Susan McDonnell

External Collaborators

  • Dr J. Whisstock, Monash University, Australia
  • Dr A Kummer, University Medical Center Utrecht, The Netherlands