Dr Sylvia Fanucchi
Telephone: 27 11 717 6348
Sylvia’s research focuses on defining the mechanism and structures of protein interactions. These interactions include protein-protein, protein-membrane and protein-DNA interactions. Structural biology (x-ray crystallography), biophysical chemistry and thermodynamics are used to characterise the relationship between the structure of the interacting molecules and the mechanism of the interaction. Currently two protein systems are being employed to study these interactions. One is the ion channel protein, CLIC1, that plays a fundamental role in the cell cycle, and the other is the nuclear transcription factor, FOXP2, that is implicated in the acquisition of language.
CLIC1 is a dual form protein that is able to exist in a soluble state in the cytoplasm where it has been shown to interact with numerous proteins and it is also able to insert into membranes where it functions as an ion channel. The objective of the CLIC project is to define the mechanism of interaction of CLIC1 with the membrane and with various cytosolic proteins which will help solve the pertinent question as to what the fundamental role is that this protein plays in the cell.
FOXP2 is a transcription factor that is of particular interest because it has been shown to have a direct link to language acquisition in humans. Study of the mechanism of interaction of this protein with DNA will yield insight into the molecular basis of language as well as associated diseases such as autism, schizophrenia and dyslexia. The FOXP2 project aims to investigate the interaction of DNA with the near full length protein as well as a truncated version containing only the forkhead domain (the DNA binding region). The FOXP subfamily is unique among FOX transcription factors in that they are believed to interact with DNA as dimers rather than monomers. Here we explore this dimerisation process and how it affects stability and DNA binding affinity and specificity. Furthermore, we study how interaction of FOXP2 with various other proteins affects structure, stability and DNA affinity. These studies all aim at better describing the complex neuromolecular mechanisms with which FOXP2 is associated.
Morris, G. and Fanucchi, S.
A key evolutionary mutation enhances DNA binding of the FOXP2 forkhead domain. Biochemistry
Blane, A. and Fanucchi, S.
The effect of pH on the DNA binding affinity of the FOXP2 forkhead domain. Biochemistry 54(25), 4001-4007
Perumal, K., Dirr, H.W. and Fanucchi, S.
Replacement of Tyr540 at the dimer interface with a phenylalanine increases the dimerisation potential of the FOXP2 forkhead domain. The protein journal 34, 111-121
Cross, M.O., Fernandes, M.A., Dirr, H. W. and Fanucchi, S.
Glutamate 85 and Glutamate 228 Contribute to the pH-Response of the Soluble Form of Chloride Intracellular Channel 1 Molecular and Cellular Biochemistry 398,83-93
Peter, B., Fanucchi, S. and Dirr, H.W.
A conserved cationic motif enhances membrane binding and insertion of the chloride intracellular channel protein 1 transmembrane domain European Biophysics Journal 43, 405-414
Peter, B., Polyansky, A., Fanucchi, S. and Dirr, H.W. (2014) A Lys−Trp Cation−π Interaction Mediates the Dimerization and Function of the Chloride Intracellular Channel Protein 1 Transmembrane Domain. Biochemistry 53: 57-67
Peter, B., Ngubane, N.C., Fanucchi, S. and Dirr, H.W. (2013)
Membrane mimetics induce helix formation and oligomerization of the chloride intracellular channel protein 1 transmembrane domain. Biochemistry 52(16):2739-49
Naicker, P. Achilonu, I., Fanucchi, S., Fernandes, M., Ibrahim, MA., Dirr,HW., Soliman, M.E. and Sayed, Y. (2012)
Structural insights into the South African HIV-1 subtype C protease: impact of hinge region dynamics and flap flexibility in drug resistance. J Biomol Struct Dyn
Legg-E'Silva, D., Achilonu, I., Fanucchi, S., Stoychev,S.H., Fernandes, M.A. and Dirr, H.W. (2012)
Role of Arginine 29 and Glutamic acid 81 Interactions in the Conformational Stability of Human Chloride Intracellular Channel 1. Biochemistry 51(40): 7854-62.
Achilonu, I., Fanucchi, S., Cross, M., Fernandes, M. and Dirr, H.W. (2012)
Role of individual histidines in the pH-dependent global stability of human chloride intracellular channel 1. Biochemistry 51, 995-1004
Parbhoo, N., Stoychev, S.H., Fanucchi , S., Achilonu, I., Adamson, R.J., Fernandes, M., Gildenhuys, S. and Dirr, H.W. (2011)
A Conserved Domain Interaction is a Determinant of Folding Cooperativity in the GST Fold. Biochemistry 50: 7067-7075.
Balchin, D., Fanucchi, S., Achilonu, I., Adamson, R.J., Burke, J., Fernandes, M., Gildenhuys, S. and Dirr, H.W. (2010)
Stability of the Domain Interface Contributes Towards the Catalytic Function at the H-site of Class Alpha Glutathione Transferase A1-1. Biochim. Biophys. Acta 1804, 2228-2233
Achilonou, I., Gildenhuys, S., Fisher, L., Burke, J., Fanucchi, S., Sewell, B.T., Fernandes, M. and Dirr, H.W. (2010)
The role of a topologically conserved isoleucine in glutathione transferase structure, stability and function. Acta Cryst, F66, 776-780
Stoychev, S.H., Nathaniel, C., Fanucchi, S., Brock, M., Li, S., Asmus, K.,
Woods, V.L. Jr. and Dirr, H.W. (2009)
Structural Dynamics of Soluble Chloride Intracellular Channel Protein CLIC1 Examined by Amide Hydrogen-Deuterium Exchange Mass Spectrometry. Biochemistry 48, 8413 – 8421
Fanucchi, S., Adamson, R.J. and Dirr, H.W. (2008)
Formation of an Unfolding Intermediate State of Soluble Chloride Intracellular Channel Protein CLIC1 at Acidic pH. Biochemistry 47, 11674 – 11681