Role of Primary Structure Variation in Structure and Function of Calcineurin

Abstract

A. fumigatus is one of the leading causes of invasive fungal infections in solid organ transplant and adult stem cell transplant recipients. It is estimated that over 20% of Americans are infected with T. gondii. T. gondii is life threatening in immunocompromised patients. Here, we study the enzyme calcineurin that is critical for the virulence and pathogenicity of these organisms. CaN is activated when calcium‐loaded calmodulin (CaM) binds the regulatory domain (RD) of the A subunit. Upon binding to CaM, the RD of human calcineurin transitions from a disordered state to an ordered state, gaining alpha helical structure. Research done in our lab has determined that the C‐terminus of the RD forms a helix (distal helix) that is necessary for the normal function of human CaN. In A. fumigatus and T. gondii, the sequence for this helix is deleted. A. fumigatus and T. gondii CaN contain modular insertions and deletions in the RD. A Ser/Pro rich region (SPRR) found in the RD that is unique to A. fumigatus is critical for the function of CaN and survival. The phosphorylation of this SPRR has also been shown to be critical in the pathogenicity of the organism. Investigations into the protein sequence of CaN of T. gondii show a unique insertion in the same area as the SPRR in A. fumigatus, but the function of this insertion is unknown. Thus, we are probing into how structure affects function through evolutionary variations.