Multi-domain proteins are ubiquitous in eukaryotic genomes but can also be formed by conjugation and by post-translational modifications (PTMs). PTMs are well acknowledged as a means to regulate the function of proteins and provide a mechanism for increasing the diversity of protein structures. It is often believed that PTMs regulate protein activity by introducing new functional groups that act as a signaling tag for binding to other molecules. We propose that PTMs may also control a protein function by modulating the protein biophysical characteristics; therefore, they can enrich the repertoire of protein characteristics beyond that dictated by their sequence. It is likely that a PTM affects the protein energy landscapes in a way that supports the function associated with that particular PTM. In our research, using computational and theoretical approaches, we focus on the effect of glycosylation and ubiquitination on the thermodynamic stability, kinetics, and local dynamics of proteins. We show that glycans can modulate the entropy and enthalpy of the unfolded state and result with higher thermostability. The effect of glycosylation on protein folding highly depends on the number of glycans attached to the protein and also on their length and flexibility as well as on the location of the conjugation sites. While, similarly to confinement or crowding effects, glycosylation affects thermostability by changing the entropy of the unfolded state, the detailed mechanism is different. Ubiquitination by unique ubiquitin polymers can induce local unwinding that may assist unfolding which is mandatory for degradation by the proteasome. Our proposal for the importance of the location of ubiquitination sites is supported by evolutionary study of large dataset of ubiquitinated proteins. Understanding the cross-talks between the protein and the conjugates at the molecular level may assist in tailoring the biophysical properties of proteins in general and modulating its cellular function.

Folding of multidomain and conjugated proteins: Intramolecular crowding effects

244th National Meeting (2012)

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