The Walter and Eliza Hall Institute of Medical Research

Dr Sandra Nicholson

Details

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Division: Inflammation

Research Overview

Our research is focussed on understanding the protein interactions and structure-function relationships, which underpin cytokine and growth factor signalling.

The natural extension of this is an interest in how these relationships may become perturbed in inflammatory and infectious disease.

Understanding the three-dimensional detail of protein complexes is crucial to the development of agents that can disrupt protein interactions and could potentially evolve into therapeutics. Structural analysis is facilitated by key collaborations with Prof Ray Norton (Monash Institute of Pharmaceutical Sciences), and colleagues in our Cancer & Haematology and Structural Biology Divisions.

The Suppressor of Cytokine Signalling (SOCS) proteins are a classic example of negative regulators, which function to regulate haematopoietic development and keep inflammatory responses in check.

Research Interests

• SOCS proteins and inflammation
• SOCS4 and SOCS5
• The SPRY domain-containing SOCS Box (SPSB; SSB) proteins

Selected Publications

1. Kuang Z, Lewis RS, Kolesnik TB, Curtis JM, Zhan Y, Saunders B, Babon JJ, Low A, Masters SL, Willson TA, Kedzierski L, Yao S, Handman E, Norton RS and Nicholson SE. The SPRY domain-containing SOCS box protein, SPSB2 targets inducible nitric oxide synthase (iNOS) for ubiquitination and proteasomal degradation. J Cell Biol 2010 190(1): 129-141. PMID: 20603330
2. Lee C, Kolesnik TB, Chakravorty A, Carter W, Alexander WS, Jones J, Anderson GP and Nicholson, SE. Suppressor of Cytokine Signaling 1 (SOCS1) is a physiological regulator of the asthma response. Clin Exp Allergy 2009 39(6): 897-907. PMID: 19309352
3. Kuang Z, Yao S, Xu Y, Lewis RS, Low A, Masters SL, Willson TA, Kolesnik TB, Nicholson SE, Garrett TJP and Norton RS. SPRY Domain-containing SOCS Box Protein 2: Crystal structure and residues critical for protein binding. J Mol Biol 2009 386: 662-674. PMID: 19154741
4. Croker BA, Kiu H and Nicholson SE. SOCS regulation of the JAK/STAT signalling pathway. Sem Cell Dev Biol 2008 19: 414-422. PMID: 18708154
5. Babon JJ, McManus EJ, Yao S, DeSouza DP, Mielke LA, Sprigg NS, Willson TA, Hilton DJ, Nicola NA, Baca M, Nicholson SE, Norton RS. The structure of SOCS3 reveals the basis of the extended SH2 domain function and identifies an unstructured insertion that regulates stability. Mol Cell 2006 22(2):205-16 PMID: 16630890
6. Masters SL, Yao S, Willson TA, Zhang JG, Palmer KR, Smith BJ, Babon JJ, Nicola NA, Norton RS, Nicholson SE. The SPRY domain of SSB-2 adopts a novel fold that presents conserved Par-4-binding residues. Nat Struct Mol Biol 2006 13(1): 77-84. PMID: 16369487
7. Nicholson SE, Metcalf D, Sprigg NS, Columbus R, Walker F, Silva A, Cary D, Willson TA, Zhang JG, Hilton DJ, Alexander WS, Nicola NA. Suppressor of cytokine signaling (SOCS)-5 is a potential negative regulator of epidermal growth factor signaling. Proc Natl Acad Sci USA 2005 102(7): 2328-33 PMID: 15695332
8. Masters SL, Palmer KR, Stevenson WS, Metcalf D, Viney EM, Sprigg NS, Alexander WS, Nicola NA, Nicholson SE. Genetic deletion of murine SPRY domain-containing SOCS box protein 2 (SSB-2) results in very mild thrombocytopenia. Mol Cell Biol 2005 25(13): 5639-47 PMID: 15964819
9. Nicholson SE, De Souza D, Fabri LJ, Corbin J, Willson TA, Zhang JG, Silva A, Asimakis M, Farley A, Nash AD, Metcalf D, Hilton DJ, Nicola NA, Baca M. Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci USA 2000 97(12): 6493-8 PMID: 10829066
10. Nicholson SE, Willson TA, Farley A, Starr R, Zhang JG, Baca M, Alexander WS, Metcalf D, Hilton DJ, Nicola NA. Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J 1999 18(2): 375-85 PMID: 9889194

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Current Laboratory Members

Faculty Member: Sandra Nicholson, BSc Mon MSc UNSW PhD Melb

Postdoctoral Fellow: Lukasz Kedzierski BSc(Hons) Mon PhD Mon

Research Assistant: Tatiana Kolesnik, BSc(Hons) MSc Nizhni Novgorod PhD Moscow

Research Assistant (Part-time): Sarah Freeman, BSc Melb

Postgraduate Student: Akshay D'Cruz, BBiomedSc(Hons) Melb

Undergraduate student: Edmond Linossi, BSc Swinburne