Structural Basis for Intramembrane Proteolysis by Rhomboid Serine Proteases

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Dec 28

PMID 17190827

Citations 86

Authors

Adam Ben-Shem

Deborah Fass

Eitan Bibi

Affiliations

Soon will be listed here.

Abstract

Intramembrane proteases catalyze peptide bond cleavage of integral membrane protein substrates. This activity is crucial for many biological and pathological processes. Rhomboids are evolutionarily widespread intramembrane serine proteases. Here, we present the 2.3-A-resolution crystal structure of a rhomboid from Escherichia coli. The enzyme has six transmembrane helices, five of which surround a short TM4, which starts deep within the membrane at the catalytic serine residue. Thus, the catalytic serine is in an externally exposed cavity, which provides a hydrophilic environment for proteolysis. Our results reveal a mechanism to enable water-dependent catalysis at the depth of the hydrophobic milieu of the membrane and suggest how substrates gain access to the sequestered rhomboid active site.

Citing Articles

Cryo-EM reveals that iRhom2 restrains ADAM17 protease activity to control the release of growth factor and inflammatory signals.

Lu F, Zhao H, Dai Y, Wang Y, Lee C, Freeman M Mol Cell. 2024; 84(11):2152-2165.e5.

PMID: 38781971 PMC: 11248996. DOI: 10.1016/j.molcel.2024.04.025.

The derlin Dfm1 couples retrotranslocation of a folded protein domain to its proteasomal degradation.

Vitali D, Fonseca D, Carvalho P J Cell Biol. 2024; 223(5).

PMID: 38448163 PMC: 11066878. DOI: 10.1083/jcb.202308074.

Effect of Environmental Factors on the Catalytic Activity of Intramembrane Serine Protease.

Asadi M, Oanca G, Warshel A J Am Chem Soc. 2022; 144(3):1251-1257.

PMID: 35023734 PMC: 10349665. DOI: 10.1021/jacs.1c10494.

Racemization in Post-Translational Modifications Relevance to Protein Aging, Aggregation and Neurodegeneration: Tip of the Iceberg.

Dyakin V, Wisniewski T, Lajtha A Symmetry (Basel). 2021; 13(3).

PMID: 34350031 PMC: 8330555. DOI: 10.3390/sym13030455.

Phosphatidylglyerol Lipid Binding at the Active Site of an Intramembrane Protease.

Bondar A J Membr Biol. 2020; 253(6):563-576.

PMID: 33210155 PMC: 7688093. DOI: 10.1007/s00232-020-00152-z.

References

Johnson A, Gautham N, Pattabhi V . Crystal structure at 1.63 A resolution of the native form of porcine beta-trypsin: revealing an acetate ion binding site and functional water network. Biochim Biophys Acta. 1999; 1435(1-2):7-21. DOI: 10.1016/s0167-4838(99)00202-2. View

Brunger A, Adams P, Clore G, DeLano W, Gros P, Grosse-Kunstleve R . Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr. 1998; 54(Pt 5):905-21. DOI: 10.1107/s0907444998003254. View

Datsenko K, Wanner B . One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc Natl Acad Sci U S A. 2000; 97(12):6640-5. PMC: 18686. DOI: 10.1073/pnas.120163297. View

Terwilliger T . Maximum-likelihood density modification. Acta Crystallogr D Biol Crystallogr. 2000; 56(Pt 8):965-72. PMC: 2792768. DOI: 10.1107/s0907444900005072. View

Ye J, Rawson R, Komuro R, Chen X, Dave U, Prywes R . ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. 2001; 6(6):1355-64. DOI: 10.1016/s1097-2765(00)00133-7. View

Lee J, Urban S, Garvey C, Freeman M . Regulated intracellular ligand transport and proteolysis control EGF signal activation in Drosophila. Cell. 2001; 107(2):161-71. DOI: 10.1016/s0092-8674(01)00526-8. View

Urban S, Lee J, Freeman M . Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell. 2001; 107(2):173-82. DOI: 10.1016/s0092-8674(01)00525-6. View

Tsruya R, Schlesinger A, Reich A, Gabay L, Sapir A, Shilo B . Intracellular trafficking by Star regulates cleavage of the Drosophila EGF receptor ligand Spitz. Genes Dev. 2002; 16(2):222-34. PMC: 155325. DOI: 10.1101/gad.214202. View

Urban S, Schlieper D, Freeman M . Conservation of intramembrane proteolytic activity and substrate specificity in prokaryotic and eukaryotic rhomboids. Curr Biol. 2002; 12(17):1507-12. DOI: 10.1016/s0960-9822(02)01092-8. View

10.

Gallio M, Sturgill G, Rather P, Kylsten P . A conserved mechanism for extracellular signaling in eukaryotes and prokaryotes. Proc Natl Acad Sci U S A. 2002; 99(19):12208-13. PMC: 129423. DOI: 10.1073/pnas.192138799. View

11.

Hedstrom L . Serine protease mechanism and specificity. Chem Rev. 2002; 102(12):4501-24. DOI: 10.1021/cr000033x. View

12.

Terwilliger T, Berendzen J . Automated MAD and MIR structure solution. Acta Crystallogr D Biol Crystallogr. 1999; 55(Pt 4):849-61. PMC: 2746121. DOI: 10.1107/s0907444999000839. View

13.

Urban S, Wolfe M . Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity. Proc Natl Acad Sci U S A. 2005; 102(6):1883-8. PMC: 548546. DOI: 10.1073/pnas.0408306102. View

14.

Lemberg M, Menendez J, Misik A, Garcia M, Koth C, Freeman M . Mechanism of intramembrane proteolysis investigated with purified rhomboid proteases. EMBO J. 2004; 24(3):464-72. PMC: 548647. DOI: 10.1038/sj.emboj.7600537. View

15.

Brossier F, Jewett T, Sibley L, Urban S . A spatially localized rhomboid protease cleaves cell surface adhesins essential for invasion by Toxoplasma. Proc Natl Acad Sci U S A. 2005; 102(11):4146-51. PMC: 554800. DOI: 10.1073/pnas.0407918102. View

16.

Maegawa S, Ito K, Akiyama Y . Proteolytic action of GlpG, a rhomboid protease in the Escherichia coli cytoplasmic membrane. Biochemistry. 2005; 44(41):13543-52. DOI: 10.1021/bi051363k. View

17.

Clemmer K, Sturgill G, Veenstra A, Rather P . Functional characterization of Escherichia coli GlpG and additional rhomboid proteins using an aarA mutant of Providencia stuartii. J Bacteriol. 2006; 188(9):3415-9. PMC: 1447467. DOI: 10.1128/JB.188.9.3415-3419.2006. View

18.

Radisky E, Lee J, Lu C, Koshland Jr D . Insights into the serine protease mechanism from atomic resolution structures of trypsin reaction intermediates. Proc Natl Acad Sci U S A. 2006; 103(18):6835-40. PMC: 1458980. DOI: 10.1073/pnas.0601910103. View

19.

Cipolat S, Rudka T, Hartmann D, Costa V, Serneels L, Craessaerts K . Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell. 2006; 126(1):163-75. DOI: 10.1016/j.cell.2006.06.021. View

20.

Brown M, Ye J, Rawson R, Goldstein J . Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell. 2000; 100(4):391-8. DOI: 10.1016/s0092-8674(00)80675-3. View