Unfolded proteins and their interactions are assuming increasing importance in studies of cellular metabolism, as functional unfolded forms of many regulatory proteins are discovered. Many disease states are linked to unfolded and misfolded proteins. Molecular chaperones frequently contain unstructured or partly structured domains whose functions are poorly understood. The first three specific aims of this project address a postulated function of these unfolded domains in binding of peptides and unfolded proteins. A novel observation from preliminary data is that in two cases these domains appear to form molten globule-type structures in solution. The first domain to be studied (Aim 1) contains the cysteine-rich (CR) and C-terminal domains of Escherichia coli DnaJ, which appears to form a molten globule. A molten globule also appears to be formed by the C-terminal domain of the E. coli chaperone trigger factor (Aim 2). In each of these cases, the structure of the molten globule state will be probed by NMR methods, and insights into the function will be provided by binding of peptides and unfolded proteins. The third domain (Aim 3) is p23, a human Hsp9O co-chaperone, whose unfolded C-terminal sequence is required for chaperone function. Constructs containing the folded N-terminal domain and the unfolded C-terminal sequence will be studied by NMR to determine the sites of binding of Hsp9O and unfolded proteins.
The fourth Aim i s concerned with a solution structural study of a quorum-sensing factor, SdiA, which has been implicated in virulence of pathogenic E. coil strains. A requirement for a small molecule autoinducer has been found before another quorum-sensing protein, TraR from Agrobacterium tumefaciens, can fold in the cellular environment. The structure and folding behavior of SdiA will be determined, in order to discover whether this behavior is general in bacterial quorum-sensing. These four specific aims are directed towards the overall goal of this research project, to elucidate the relationship of structure and function in protein systems with one or more unfolded components, in order to further our understanding of the role of folding and unfolding reactions in cellular metabolism and disease.
| Dyson, H Jane; Wright, Peter E (2017) How Does Your Protein Fold? Elucidating the Apomyoglobin Folding Pathway. Acc Chem Res 50:105-111 |
| Lim, Kwang Hun; Dyson, H Jane; Kelly, Jeffery W et al. (2013) Localized structural fluctuations promote amyloidogenic conformations in transthyretin. J Mol Biol 425:977-88 |
| Dyson, H Jane (2012) Roles of intrinsic disorder in protein-nucleic acid interactions. Mol Biosyst 8:97-104 |
| Zhu, Jing; Martinez-Yamout, Maria; Cardoso, Rosa et al. (2012) Homodimerization of the PAS-B domains of hypoxia-inducible factors. J Phys Chem B 116:6960-5 |
| Park, Sung Jean; Kostic, Milka; Dyson, H Jane (2011) Dynamic Interaction of Hsp90 with Its Client Protein p53. J Mol Biol 411:158-73 |
| Dyson, H Jane (2011) Expanding the proteome: disordered and alternatively folded proteins. Q Rev Biophys 44:467-518 |
| Park, Sung Jean; Borin, Brendan N; Martinez-Yamout, Maria A et al. (2011) The client protein p53 adopts a molten globule-like state in the presence of Hsp90. Nat Struct Mol Biol 18:537-41 |
| Wright, Peter E; Dyson, H Jane (2009) Linking folding and binding. Curr Opin Struct Biol 19:31-8 |
| Fuller, Amelia A; Du, Deguo; Liu, Feng et al. (2009) Evaluating beta-turn mimics as beta-sheet folding nucleators. Proc Natl Acad Sci U S A 106:11067-72 |
| Danielsson, Jens; Liljedahl, Leena; Barany-Wallje, Elsa et al. (2008) The intrinsically disordered RNR inhibitor Sml1 is a dynamic dimer. Biochemistry 47:13428-37 |
Showing the most recent 10 out of 36 publications
