A series of protein molecules present on the surface of cells in the body tightly regulate activation of the complement system and prevent damage. (Representational)A new study has raised hopes for developing therapeutics for the pathological conditions involving the complement system, the part of the immune system responsible for fighting infections. The study has implications for the development of therapeutic interventions for Alzheimer’s disease, stroke, age-related macular degeneration, asthma, rheumatoid arthritis and cancer.
The study was conducted at the city-based National Centre for Cell Science (NCCS) and published in the American journal Proceedings of the National Academy of Sciences. The complement system, which is involved in immune surveillance, is an important component of the innate immune system. Efficient functioning of the system is crucial to protect the body from infections. But lack of proper regulation of this system can result in damage to the cells of the host body by its own complement system, which can lead to several diseases, including Alzheimer’s disease, stroke, age-related macular degeneration, asthma, rheumatoid arthritis and cancer.
Dr Arvind Sahu, NCCS senior scientist and one of the authors of the study, said the study has identified the precise units of the regulators of complement activation (RCA) protein molecules that are responsible for their regulatory function. This reveals that functional modularity exists in these proteins, he said.
A series of protein molecules present on the surface of cells in the body tightly regulate activation of the complement system and prevent damage. These proteins belong to a family called the regulators of complement activation (RCA) family. The members of the RCA family of proteins are responsible for preventing damage to the host’s cells by its own complement, which is effected through two regulatory mechanisms called decay accelerating activity (DAA) and cofactor activity (CFA).
Understanding the nuts and bolts of how the DAA and CFA mechanisms operate could help gain useful insights into what goes wrong in diseases linked to inappropriate regulation of the complement system, and could thus help design improved strategies for therapeutic interventions, Sahu added.
These complement regulators have been the target of research, which has led to the discovery that they are composed of a string of multiple units, like beads strung together. But which of these units or beads are specifically required for these proteins to carry out their respective functions was so far unknown, and whether these specific units could be joined together to form a larger molecule with both functions combined together had not been explored.
The results of the study have demonstrated that the basic functional blocks (domains) in these proteins that enable complex activities like DAA and CFA are formed of only two units, which are arranged in a specific order. The study has demonstrated that it is possible to artificially link the identified functional domains of the proteins responsible for the DAA and CFA to create a molecule with both these activities combined together, which they have named ‘decay-cofactor protein (DCP).
These findings have important implications since such a regulatory protein with dual-activity could serve as a lead molecule for developing RCA-based therapeutics for treating pathological conditions associated with faulty regulation of the complement system. The research team included his PhD students Hemendra Singh Panwar, Hina Ojha and Sunil Raut, and colleagues from the Bioinformatics Centre, S P Pune University (Payel Ghosh, and the Amity Institute of Biotechnology, Mumbai (Sagar H Barage).
