Date: 18-February-2004 Source: Press Release from Institute of Molecular and Cell Biology (IMCB) Researchers from the Institute of Molecular and Cell Biology (IMCB) have successfully mapped the atomic structure of a protein that is crucial to a cell's ability to read signals correctly and weed out aberrant genetic instructions. That protein may be the key to combating genetic disorders such Cystic Fibrosis and Duchenne Muscular Dystrophy. Altogether, there are about 200 human genetic diseases that result from faulty genetic signals being relayed to cells. The IMCB research, led by Dr Song Haiwei, focused on structural studies on the yeast protein, Dcp1p. The findings are published in the March issue of the scientific journal Nature Structural and Molecular Biology (NSMB). Explaining the significance of the work, Dr Song said, "Many diseases happen because biological molecules undergo changes in structure and can no longer function properly. Structural Biology enables us to understand how a molecule is put together and also how it works and interacts with other molecules. As a result, Structural Biology has become important to every area of Biology." How do faulty signals give rise to genetic disorders? When functioning normally, a cell is able to translate genetic instructions encoded in its DNA (deoxyribonucleic acid) into thousands of functional proteins. In order to do this, a cell must first scan and survey the incoming signals and interpret them correctly, producing temporary messages in the form of mRNAs (messenger ribonucleic acid) that relay the DNA code to the cell's protein-making factories. In some genetic disorders, the ability to read signals correctly is impaired and the cell is unable to weed out aberrant genetic instructions. Nonsense instructions are then accepted, resulting in shortened protein molecules that are harmful to the cell. In the IMCB study, graduate student She Meipei and her supervisor Dr Song Haiwei, in collaboration with Dr Roy Parker's lab at the Howard Hughes Medical Institute in Arizona, USA, conducted structural studies on the yeast protein, called Dcp1p. The researchers found that Dcp1p takes part in the complex series of events leading to the destruction of rogue mRNA. The Dcp1p protein removes a chemical "cap" from one end of the mRNA molecule, making it open to attack by protein digesting enzymes called Exonucleases. But how does it function? The researchers showed that structurally, the Dcp1p protein belongs to a protein family called EVH1-containing proteins. All members of this family contain one particular structural element called the EVH-1 domain, which is critical for protein-protein binding and the assembly of protein complexes. Such protein complexes may prove necessary for de-capping to take place.

The researchers also found that Dcp1p contains two sites within its EVH1 domain that are absolutely required for its function. One of those sites (Patch 1) is thought to be a binding site for regulatory proteins that control mRNA de-capping within the cell. The other site, called Patch 2, is required for Dcp1p's de-capping ability. If this site is mutated, de-capping activity of Dcp1p declines severely. This is Dr Song's second NSMB paper within three months, and illustrates the fundamental importance of Structural Biology. For more information please contact: Dr SONG Haiwei, Principal Investigator, Institute of Molecular and Cell Biology, 30, Medical Drive, Singapore 117609, Tel: 65-6872-7077 Fax: 65-6779-1117 Email: haiwei@imcb.nus.edu.sg Or Mr Joshua WOO, Administration Officer, Institute of Molecular and Cell Biology, 30, Medical Drive, Singapore 117609, Tel: 65-68748604 Email: woohk@imcb.a-star.edu.sg Notes to the Editor: The research findings described in this press release can be found in the March 2004 issue of the scientific journal Nature Structural and Molecular Biology under the title "Crystal Structure of Dcp1p and its functional implications in mRNA decapping" Authors: Meipei She, Carolyn J Decker, Kumar Sundramurthy, Yuying Liu, Nan Chen, Roy Parker and Haiwei Song. Laboratory of Macromolecular Structure, Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Republic of Singapore. More images of Dcp1p structure are available upon request. Useful websites: Dr Song's Laboratory web-page: http://www.imcb.a-star.edu.sg/research/ research_group/structural_biology/6000000111_article.html Dr Parker's Laboratory web-page: http://www.mcb.arizona.edu/parker/ About the Institute of Molecular and Cell Biology (IMCB) The Institute of Molecular and Cell Biology (IMCB) is a member of Singapore's Agency for Science, Technology and Research (A*STAR). It is a world-class research institute in biomedical sciences with core strengths in cell cycling, cell signalling, cell death, cell motility and protein trafficking. Its recent achievements include being part of an international consortium that successfully sequenced the entire pufferfish (Fugu) genome - a world first. The IMCB was also awarded the Nikkei Prize 2000 for Technological Innovation in recognition of its growth into a leading international research centre and its collaboration with industry and research institutes worldwide. Established in 1987, the Institute currently has 38 independent research groups with more than 400 staff members. IMCB website: http://www.imcb.a-star.edu.sg A*STAR website: http://www.a-star.edu.sg