The objective of this project is to understand the function of SAM domains. SAM domains are frequently occurring protein modules that bind to themselves, to other SAM domains and to other non-SAM domain containing proteins. They are important for building regulatory protein complexes in the cell. Our work in the prior grant period has demonstrated that SAM domains can form a diverse array of oligomers, ranging from polymeric structures to discrete, closed oligomers. We have obtained high-resolution structures of three different SAM polymers, but this only represents a fraction of the different protein interaction modes utilized by SAM domains. In the current application, we propose to: Determine the structures of three more polymers, a structure of a hetero-polymeric ioint made by two different SAM domains, and the structure of discrete oliqomer. These structures will reveal new modes of SAM interactions. Investigate the role of SAM polymerization in transcriptional repression. We have discovered that many repressors contain polymeric SAM domains. We hypothesize that the SAM polymers play a role in the spreading of transcriptional repression and proposed a model of silenced chromatin structure, organized around a SAM polymer. We plan to test these ideas in this proposal. Test a new anti-leukemia drug strategy. The TEL gene is frequently involved in chromosomal translocations, leading to oncogenic fusions of the TEL-SAM domain to a variety of other protein domains including protein tyrosine kinases. TEL-SAM polymerization leads to constitutive activation of these tyrosine kinases, which in turn leads to a variety of hematalogic malignancies. We have developed protein inhibitors of TEL-SAM polymerization and plan to test whether these inhibitors can block cell transformation by the TEL oncogenes.
| Knight, Mary Jane; Joubert, Marisa K; Plotkowski, Megan L et al. (2010) Zinc binding drives sheet formation by the SAM domain of diacylglycerol kinase ýý. Biochemistry 49:9667-76 |
| Di Pietro, Santiago M; Cascio, Duilio; Feliciano, Daniel et al. (2010) Regulation of clathrin adaptor function in endocytosis: novel role for the SAM domain. EMBO J 29:1033-44 |
| Joh, Nathan Hyunjoong; Min, Andrew; Faham, Salem et al. (2008) Modest stabilization by most hydrogen-bonded side-chain interactions in membrane proteins. Nature 453:1266-70 |
| Harada, Bryan T; Knight, Mary Jane; Imai, Shin-Ichi et al. (2008) Regulation of enzyme localization by polymerization: polymer formation by the SAM domain of diacylglycerol kinase delta1. Structure 16:380-7 |
| Nauli, Sehat; Farr, Saman; Lee, Yueh-Jung et al. (2007) Polymer-driven crystallization. Protein Sci 16:2542-51 |
| Qiao, Feng; Harada, Bryan; Song, Haiyun et al. (2006) Mae inhibits Pointed-P2 transcriptional activity by blocking its MAPK docking site. EMBO J 25:70-9 |
| Gundelfinger, Eckart D; Boeckers, Tobias M; Baron, Marisa K et al. (2006) A role for zinc in postsynaptic density asSAMbly and plasticity? Trends Biochem Sci 31:366-73 |
| Baron, Marisa K; Boeckers, Tobias M; Vaida, Bianca et al. (2006) An architectural framework that may lie at the core of the postsynaptic density. Science 311:531-5 |
| Bowie, James U (2006) Flip-flopping membrane proteins. Nat Struct Mol Biol 13:94-6 |
| Kim, Chongwoo A; Sawaya, Michael R; Cascio, Duilio et al. (2005) Structural organization of a Sex-comb-on-midleg/polyhomeotic copolymer. J Biol Chem 280:27769-75 |
Showing the most recent 10 out of 16 publications
