Scientists at National Centre for Biological Sciences (NCBS) have discovered a new twist to a crucial signalling pathway, involved in development, based on the protein Hedgehog. This pathway could possibly have an impact on future cancer research.

Hedgehog signals play crucial roles in tissue-patterning and their dysregulation could be very important in generation of some cancers. Therefore, this research could be significant in terms of diagnosis and treatment of this dreaded disease, Dr Satyajit Mayor, heading the research team of the study at the National Centre for Biological Sciences told Pharmabiz.

The multidisciplinary research was mainly driven by Neha Vyas working with Debanjan Goswami at NCBS and supported by Dr Shashidhara's laboratory at the Centre for Cellular and Molecular Biology (CCMB), Hyderabad. Neha, a PhD student at Mysore University under Prof HL Ranganath, is a cell and developmental biologist and Debanjan Goswami, is a biophysicist. Both worked together in Satyajit Mayor's lab, took their cues from NCBS bioinformatic expert Prof R Sowdhamini and developmental biologist Prof Vijay Raghavan. The researchers were able to predict which of the Hedgehog's amino acids were most likely to set up the electrostatic interaction. They used a directed mutation to deactivate one of the main suspects which is a single lysine residue. The normal mega-clusters did not form and the long-range developmental effects so typical of Hedgehog were shut down.

According to Dr Mayor, the pathway kicks off when several unattached Hedgehog proteins are drawn together by electrostatic interactions between amino acids at the proteins' periphery. The nanoscale cluster that forms is the first seed of a multi-stage aggregation process. This yields as a mature Hedgehog mega-cluster, capable of transport and signalling at a long range from its site of production. This is a hallmark of a tissue patterning morphogen.

The bioinformatics contribution was in identifying which residue could be crucial for the interprotomer interface. A single residue mutation was designed on the basis of the bioinformatics modelling and analysis of conserved residues. Detailed modelling and recognition of possible interaction poses took maximum time in this bioinformatics work. The analysis of conserved residues on the modelled protein and selection of site for mutation took relatively less time, stated Dr Sowdhamini, bioinformatics department, NCBS.

"Future efforts could be to obtain accurate structure determination of hedgehog multimer and to design further (double) mutations that could have a rescue effect in long-range signalling. The modelling of a single hedgehog molecule was not difficult in this project. However, modelling the interactions between hedgehog domains was challenging. The design of single residue mutation was largely guided by conservation of residues when compared with many hedgehog sequences, informed Dr Sowdhamini

Identifying this initial step might help other scientists to design an anti-cancer drug that could stall a mutant Hedgehog pathway in the most effective way possible. Ways to restrict the Hedgehog pathway have been sought ever since it was realized that natural mutation-based errors can actually over-activate the Hedgehog circuit, resulting in cancers like the small cell lung, pancreatic and prostrate cancers which are that are very malignant and difficult to treat. But as yet no Hedgehog antagonist has been cleared for human use and the most promising candidate, cyclopamine, does not target Hedgehog itself, but a secondary protein of the pathway.