Protein stability and dynamics in cancer-associated NQO1, a model for loss-of-function genetic diseases – Biologisk Institut - Københavns Universitet

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Protein stability and dynamics in cancer-associated NQO1, a model for loss-of-function genetic diseases

Speaker: Dr Angel L. Pey, Assistant Professor, Department of Physical Chemistry, University of Granada (Spain)

Host: Postdoc Amelie Stein, Section for Biomolecular Sciences

Abstract
Missense mutations cause thousands of diseases affecting millions of people world-wide. This represents a substantial burden at human, social and economical levels. Frequently, these mutations alter protein stability (and dynamics!?) consequently decreasing protein functionality in vivo and perturbing homeostasis. Importantly, these alterations induced by mutations may translate into loss of function through different mechanisms (inactivation, accelerated degradation, altered protein:protein interactions..), although how molecular changes in protein structure, stability (and dynamics!?) are translated into intracellular loss-of-function is not well known.

We will present our efforts to understand the links between altered protein molecular properties and intracellular aberrant behavior in disease-causing mutations. To do so, we will use as a model the common cancer-associated polymorphism P187S in the NQO1 enzyme, which accelerates intracellular protein degradation and leads to enzyme inactivation [1-5]. NQO1 is also a paradigm for the control exerted by flavin bioavailability on the intracellular stability of the human flavoproteome [6]. We will show how P187S causes dynamic alterations in two functional sites far from the mutation: the FAD binding site, thus decreasing activity, and the C-terminal domain which lead to increased ubiquitylation and fast degradation by the proteasome [1-3, 6]. Then, we will show how two evolutionary divergent suppressor mutations (H80R and E247Q) are capable of rescuing P187S function and stability in vitro and in cells, through long-range (epistatic) communication of their stabilizing effects which remodels the structure and dynamics of altered functional sites [4-5]. To end, we will show that the molecular and cellular phenotypes of WT and P187S are strongly affected by phosphorylation at S82, while the H80R mutation strongly counterbalances these effects. We will discuss the implications of our work for the understanding of disease genotype-phenotype relationships, their treatment with pharmacological chaperones and the divergence of disease phenotypes among mammalian species.