Enhanced structure prediction of gene products containing class III adenylyl cyclase domains

Domain finding algorithms are useful to understand overall domain architecture and to propose biological function to gene products. Automated methods of applying these tools to large-scale genome studies often employ stringent thresholds to recognize sequence domains. The realization of additional domains can be tedious involving manual intervention but can lead to better understanding of overall biological function. We propose a multi-step approach for the further examination of unassigned linker regions that exploits properties such as the conservation of domain architectures of homologous proteins to propose connections. Improved structure prediction is possible starting from initial domain architectures, obtained from simple 'domain finding' techniques, by concentrating on connecting unassigned regions. 254 unassigned regions have been examined in 114 gene products that potentially contain at least one class III adenylyl cyclase domain for a pilot study. Reliable structure prediction was possible for nearly 80% of unassigned regions. New connections were recognized that assign putative structure and function to these regions by indirect searches (26%). Several others (34%) could be associated with three-dimensional models that might pertain to novel folds and new functions with enough structural content and evolutionary conservation. The presence of additional domains will provide further clues to the overall function of the gene products and their recruitment in particular biochemical pathways.