Leucine-Rich Repeat Domains in the Class III Adenylyl Cyclase of Fungi: Some Features of the Sequences and Structures

Fungal adenylyl cyclase (AC) converts adenosine triphosphate (ATP) to the second messenger 3′,5′-cyclic AMP (cAMP). Class III ACs contain multiple domains, including the adenylyl cyclase domain and a leucine-rich repeat domain (LRR), through which multiple signals are integrated into the cAMP-Protein Kinase A (PKA) signaling response. This review focuses on the sequences and structural features of the LRR domains. To this end, we analyzed LRR domain sequences from ACs in the phyla Ascomycota, Mucoromycota, Basidiomycota, Blastocladiomycota, Zoopagomycota, and Chytridiomycota. Protein structures were also predicted using AlphaFold2. More than 99% of individual LRR domains consist of 23 repeats with an additional parallel β-strand at the C-terminus. The repeat unit length (RUL) is mainly 23 or 24 residues. The most distinctive feature is the presence of non-LRR island region (IR) interrupting the LRRs between the 16th and the 17th units. The IRs may be roughly classified into two groups. The first group IRs, which, for example, are identified in ACs from Saccharomyces cerevisiae and Candida albicans belonging to the phylum Ascomycota, are relatively short; the IR lengths are within 10 to 50 residues. The second group IRs, which are identified in many ACs from the phyla Ascomycota, Mucoromycota, Basidiomycota, and Zoopagomycota are long; the IRs range from 50 to 220 residues. Most of the long IRs are regarded as intrinsically disordered regions. The AC LRR domains adopt typical solenoid structures in which the IRs form bulges or loops in a non-globular conformation. Two possibilities are discussed for the role of IRs in AC LRR domains. This review proposes a new subclass of fungal class III ACs, which includes a forkhead-associated domain.