3S0X

The crystal structure of GxGD membrane protease FlaK

Summary for 3S0X

• Entry DOI: 10.2210/pdb3s0x/pdb
• Descriptor: Peptidase A24B, FlaK domain protein (1 entity in total)
• Functional Keywords: preflagellin peptidase, gxgd protease, aspartyl protease, intramembrane proteolysis, membrane protein, hydrolase
• Biological source: Methanococcus maripaludis
• Total number of polymer chains: 2
• Total formula weight: 54152.83

Authors

Hu, J.,Xue, Y.,Ha, Y. (deposition date: 2011-05-13, release date: 2011-07-20, Last modification date: 2024-10-16)

Primary citation

Hu, J.,Xue, Y.,Lee, S.,Ha, Y.
The crystal structure of GXGD membrane protease FlaK.
Nature, 475:528-531, 2011

PubMed Abstract: The GXGD proteases are polytopic membrane proteins with catalytic activities against membrane-spanning substrates that require a pair of aspartyl residues. Representative members of the family include preflagellin peptidase, type 4 prepilin peptidase, presenilin and signal peptide peptidase. Many GXGD proteases are important in medicine. For example, type 4 prepilin peptidase may contribute to bacterial pathogenesis, and mutations in presenilin are associated with Alzheimer's disease. As yet, there is no atomic-resolution structure in this protease family. Here we report the crystal structure of FlaK, a preflagellin peptidase from Methanococcus maripaludis, solved at 3.6 Å resolution. The structure contains six transmembrane helices. The GXGD motif and a short transmembrane helix, helix 4, are positioned at the centre, surrounded by other transmembrane helices. The crystal structure indicates that the protease must undergo conformational changes to bring the GXGD motif and a second essential aspartyl residue from transmembrane helix 1 into close proximity for catalysis. A comparison of the crystal structure with models of presenilin derived from biochemical analysis reveals three common transmembrane segments that are similarly arranged around the active site. This observation reinforces the idea that the prokaryotic and human proteases are evolutionarily related. The crystal structure presented here provides a framework for understanding the mechanism of the GXGD proteases, and may facilitate the rational design of inhibitors that target specific members of the family.

PubMed: 21765428
DOI: 10.1038/nature10218

Experimental method

X-RAY DIFFRACTION (3.6 Å)