PROTEIN CONFORMATION SAMPLING USING ENERGY LANDSCAPE APPROACH

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In mammalian cells, proteins are initially expressed as hetero-polymers with 20 types of different amino acids. Proteins, however, often need more varieties of subunits. This greater diversity is achieved by covalent post-translational modifications such as glycosylation, methylation, or nucleotidylation. These modifications can lead to conformational changes of the proteins by perturbing their energy landscape and thereby altering their functions. In this paper, we address the energetic and structural consequence of one of the most important forms of reversible modification: phosphorylation. In phosphopeptides, the side chain polar hydrogens of serine, threonine, tyrosine, and histidine can be replaced by phosphoryl groups. Phosphorylation occurs quite frequently in signal transduction regulation and is increasingly being noticed throughout the genome due to the advancements of mass spectrometry. Direct structural modifications not only may affect protein-protein interactions, but can allow conformational switches to be constructed using single domain proteins. Using the NFAT regulatory domain as an example, we show these changes can not only modify the secondary structure of the protein locally but also globally alter protein tertiary structure, thus allowing phosphorylation to reset the switch.