Paper Alert: 3D Structure of γ-Secretase

In this week’s PNAS online, researchers at Dennis Selkoe’s lab at Harvard University, and Huilin Li’s lab at Brookhaven National Laboratory, Upton, New York, report the 3D structure of purified γ-secretase. Minji Kim, Alice Lu, and Rudy Tanzi, Massachusetts General Hospital, first brought us news of this structure as part of their coverage of the Keystone Symposia Meeting held last February. As that summary revealed, first author Vlado Lazarov and colleagues used the electron microscope to determine that γ-secretase exists as a particle 120 Angstroms in length with an internal cylindrical chamber about 20-40 Angstroms long. The structure has ~20 Angstrom openings at the top and bottom, which could conceivably allow exit of cleavage products to the extracellular and intracellular milieus. A supporting movie, showing the pores, is available for download at the PNAS website.—Tom Fagan

Comments

  1. This is a very daring structural proposal, which will stimulate and spark many discussions. The monomeric rhodopsin structure imposes significant problems for the homology modelling of dimeric GPCRs. Here it is employed for the structure prediction of a far more complex system involving additional TM domains and many protein protein interactions. The supporting movie displays a very appealing pore, but the substrate must enter from the side. Furthermore, this pore must be regulated or blocked under normal conditions, otherwise it would be an unregulated aqueaporin with a giant opening. Further structures based on Asp KOs may be "caught in the act" with the substrate.

    View all comments by Boris Schmidt

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References

News Citations

  1. Keystone Symposia Meeting, Part 4—Presenilin and γ-secretase

External Citations

  1. PNAS website

Further Reading

Primary Papers

  1. Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H. Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores. Proc Natl Acad Sci U S A. 2006 May 2;103(18):6889-94. PubMed.

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