A goal of several projects was to determine the sequence-structure-function relationship of proteins with internal tandem repeats. In particular, sequence profiles were made to search sequence databases for arrays of tandem repeats in proteins of cell cycle regulation. Based on this analysis, toroidal alpha-helical models were suggested for the largest protein subunits Rpn1 and Rpn2 of 26S proteasome. Furthermore, it was proposed that Rpn1 and Rpn2 toroids are aligned along the common axial pores of the ATPase hexamer and form an antechamber of the 26S proteasome. It was also suggested that the function of this antechamber is to aid the ATPases in the unfolding of protein substrates prior to proteolysis. This result provides insight into the molecular mechanism of cell cycle regulation. In other work, we assessed the ability to model proteins with leucine-rich repeats (LRR) in light of the latest structural information by comparing models with the recently determined crystal structures. The comparison suggests that the general architecture, curvature, """"""""interior/exterior"""""""" orientations of side chains, and backbone conformation of the LRR structures can be predicted correctly. The reliability of the LRR protein modeling suggests that it would be informative to apply similar modeling approaches to other classes of solenoid proteins. One of the projects deals with the structural arrangement of human cell envelopes and cornified epithelial cells of skin. The majority of the cell envelope proteins have sequence repeats. Possible three-dimensional structures of known proteins of the human cell envelope and their interactions with each other were analyzed. A mode of interaction between involucrin and small proline-rich proteins of the skin was suggested. Several projects involving the molecular modeling of globular proteins and the docking of their substrates were performed. For example, a red fluorescence protein was modeled in order to understand molecular processes occurring in """"""""fluorescent timers,"""""""" proteins that change color with time. An ongoing project concerns molecular docking of peptide substrates in the active site of the transglutaminase enzyme. Based on this docking, a specificity of the substrate binding is suggested. This will improve our understanding of the regulation of cross-linking of cell envelope proteins by this enzyme. In another project, the three-dimensional structure of the C-terminal part of atypical transcription factor Prospero was predicted and modeled. The relation between the model and known experimental data on its nuclear transport was analyzed. Finally, modeling of the complex between GalR repressor and HU protein allowed us to suggest several sites of mutations.

Agency
National Institute of Health (NIH)
Institute
Center for Information Technology (CIT)
Type
Intramural Research (Z01)
Project #
1Z01CT000259-07
Application #
6675523
Study Section
(CMM)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Computer Research and Technology
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Henry, L Keith; Field, Julie R; Adkins, Erika M et al. (2006) Tyr-95 and Ile-172 in transmembrane segments 1 and 3 of human serotonin transporters interact to establish high affinity recognition of antidepressants. J Biol Chem 281:2012-23
Kajava, Andrey V; Kobe, Bostjan (2002) Assessment of the ability to model proteins with leucine-rich repeats in light of the latest structural information. Protein Sci 11:1082-90
Kalinin, Andrey E; Kajava, Andrey V; Steinert, Peter M (2002) Epithelial barrier function: assembly and structural features of the cornified cell envelope. Bioessays 24:789-800
Terskikh, Alexey V; Fradkov, Arkady F; Zaraisky, Andrey G et al. (2002) Analysis of DsRed Mutants. Space around the fluorophore accelerates fluorescence development. J Biol Chem 277:7633-6
Kajava, A V; Cheng, N; Cleaver, R et al. (2001) Beta-helix model for the filamentous haemagglutinin adhesin of Bordetella pertussis and related bacterial secretory proteins. Mol Microbiol 42:279-92
Kobe, B; Kajava, A V (2001) The leucine-rich repeat as a protein recognition motif. Curr Opin Struct Biol 11:725-32
Kajava, A V (2001) Review: proteins with repeated sequence--structural prediction and modeling. J Struct Biol 134:132-44
Potekhin, S A; Melnik, T N; Popov, V et al. (2001) De novo design of fibrils made of short alpha-helical coiled coil peptides. Chem Biol 8:1025-32
Spirina, O; Bykhovskaya, Y; Kajava, A V et al. (2000) Heart-specific splice-variant of a human mitochondrial ribosomal protein (mRNA processing; tissue specific splicing). Gene 261:229-34
Kajava, A V (2000) alpha-Helical solenoid model for the human involucrin. FEBS Lett 473:127-31

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