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Structural Basis for the Magnesium-Dependent Activation and Hexamerization of the Lon AAA+ Protease
- Source :
- Structure. 24:676-686
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- The Lon AAA+ protease (LonA) plays important roles in protein homeostasis and regulation of diverse biological processes. LonA behaves as a homomeric hexamer in the presence of magnesium (Mg(2+)) and performs ATP-dependent proteolysis. However, it is also found that LonA can carry out Mg(2+)-dependent degradation of unfolded protein substrate in an ATP-independent manner. Here we show that in the presence of Mg(2+) LonA forms a non-secluded hexameric barrel with prominent openings, which explains why Mg(2+)-activated LonA can operate as a diffusion-based chambered protease to degrade unstructured protein and peptide substrates efficiently in the absence of ATP. A 1.85 Å crystal structure of Mg(2+)-activated protease domain reveals Mg(2+)-dependent remodeling of a substrate-binding loop and a potential metal-binding site near the Ser-Lys catalytic dyad, supported by biophysical binding assays and molecular dynamics simulations. Together, these findings reveal the specific roles of Mg(2+) in the molecular assembly and activation of LonA.
- Subjects :
- 0301 basic medicine
medicine.medical_treatment
Proteolysis
Peptide
Plasma protein binding
Biology
Random hexamer
Bortezomib
Mitochondrial Proteins
03 medical and health sciences
ATP-Dependent Proteases
Structural Biology
Hydrolase
medicine
Homomeric
Magnesium
Protease Inhibitors
Binding site
Molecular Biology
chemistry.chemical_classification
Binding Sites
Protease
medicine.diagnostic_test
Molecular Docking Simulation
030104 developmental biology
chemistry
Biochemistry
Biophysics
Protein Multimerization
Protein Binding
Subjects
Details
- ISSN :
- 09692126
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Structure
- Accession number :
- edsair.doi.dedup.....ce6a945fb015dc6bb1287b5627a05873