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Structure of a presenilin family intramembrane aspartate protease

Abstract

Presenilin and signal peptide peptidase (SPP) are intramembrane aspartyl proteases that regulate important biological functions in eukaryotes. Mechanistic understanding of presenilin and SPP has been hampered by lack of relevant structural information. Here we report the crystal structure of a presenilin/SPP homologue (PSH) from the archaeon Methanoculleus marisnigri JR1. The protease, comprising nine transmembrane segments (TMs), adopts a previously unreported protein fold. The amino-terminal domain, consisting of TM1–6, forms a horseshoe-shaped structure, surrounding TM7–9 of the carboxy-terminal domain. The two catalytic aspartate residues are located on the cytoplasmic side of TM6 and TM7, spatially close to each other and approximately 8 Å into the lipid membrane surface. Water molecules gain constant access to the catalytic aspartates through a large cavity between the amino- and carboxy-terminal domains. Structural analysis reveals insights into the presenilin/SPP family of intramembrane proteases.

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Figure 1: Overall structure of a presenilin/SPP homologue from the archaeon Methanoculleus marisnigri JR1 (PSH).
Figure 2: Topology diagrams of PSH and other families of intramembrane proteases.
Figure 3: Conformation of the active site.
Figure 4: Homology modelling of human presenilin 1.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

The atomic coordinates and structure factor files of PSH have been deposited in the Protein Data Bank with the accession codes 4HYG, 4HYD and 4HYC, respectively, for the space groups C222, C2221 and P2.

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Acknowledgements

We thank J. He and Q. Wang at Shanghai Synchrotron Radiation Facility beamline BL17U and K. Hasegawa and T. Kumasaka at the SPring-8 beamline BL41XU for assistance. This work was supported by funds from the Ministry of Science and Technology (grant number 2009CB918801), and National Natural Science Foundation of China project 30888001.

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X.L., S.D. and Y.S. designed all experiments. X.L., S.D., C.Y., X.G. and J.W. performed the experiments. All authors contributed to data analysis. X.L., S.D., X.G., J.W. and Y.S. contributed to manuscript preparation. Y.S. wrote the manuscript.

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Correspondence to Yigong Shi.

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The authors declare no competing financial interests.

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Li, X., Dang, S., Yan, C. et al. Structure of a presenilin family intramembrane aspartate protease. Nature 493, 56–61 (2013). https://doi.org/10.1038/nature11801

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