Stanford Synchrotron Radiation Lightsource
Date Published: November 03, 2008

Role of Specific Protein Mutations in Causing Human Disease Revealed
summary written by Brad Plummer, SLAC Communication Office

Scientists are one step closer to understanding a piece of the machinery involved in DNA transcription and repair, thanks to work done in part at the SSRL macromolecular crystallography Beam Line 11-1. The team, led by The Scripps Research Institute researcher John Tainer, and colleagues worked out the structure of an important enzyme call XPD, a member of the helicase family of enzymes, found in all living organisms. The results were published in the May 2008 edition of the journal Cell.

In eukaryotes, XPD is responsible for unwinding double-stranded DNA molecules during transcription or repair. Because it plays such a key role in the DNA transcription and repair pathways, determining the structure of XPD is crucial to understanding how healthy cells operate and how defects lead to disease. Mutations in the XPD protein are associated with cancer and premature aging (progeria).

Human XPD has proved an elusive target for crystallographic studies because it is difficult to synthesize in sufficient quantities. Working with an XPD homolog from the single-celled Sulfolobus acidocaldarius, the team confirmed evidence from earlier experiments that suggested one of the four domains of the XPD structure contains an iron-sulfur containing cluster, and provided for the first time the structural basis to explain the mutations for three distinguished inherited diseases.

To learn more about this research see the full Scientific Highlight

L. Fan, J.O. Fuss, Q.J. Cheng, A.S. Arvai, M. Hammel, V.A. Roberts, P.K. Cooper and J.A. Tainer, "XPD helicase structures and activities: insights into the cancer and aging phenotypes from XPD mutations", Cell 133 (2008), pp. 789-800

SLAC National Accelerator Laboratory
Stanford University