Abstract
The M42 aminopeptidases are dinuclear aminopeptidases displaying a peculiar tetrahedron-shaped structure with 12 subunits. Their quaternary structure results from the self-assembly of six dimers controlled by their divalent metal ion cofactors. The oligomeric-state transition remains debated despite the structural characterization of several archaeal M42 aminopeptidases. The main bottleneck is the lack of dimer structures, hindering the understanding of structural changes occurring during the oligomerization process. We present the first dimer structure of an M42 aminopeptidase, TmPep1050 of Thermotoga maritima, along with the dodecamer structure. The comparison of both structures has allowed us to describe how the metal ion cofactors modulate the active-site fold and, subsequently, affect the interaction interface between dimers. A mutational study shows that the M1 site strictly controls dodecamer formation. The dodecamer structure of TmPep1050 also reveals that a part of the dimerization domain delimits the catalytic pocket and could participate in substrate binding.
Highlights
The M42 aminopeptidases are dinuclear aminopeptidases displaying a peculiar tetrahedron-shaped structure with 12 subunits
High-resolution structures of P. horikoshii PhTET2 have revealed that the M42 aminopeptidase subunit is composed of an ␣/ catalytic domain and a PDZ-like dimerization domain [13, 15]
The metal ions have been described to bind the substrate, to facilitate nucleophile generation, and to stabilize the transition state of peptide hydrolysis [32]. In addition to their catalytic roles, the metal ions could control the TET aminopeptidase oligomerization. Such a structural role has been reported for three M42 aminopeptidases, PhTET2 and PhTET3 from P. horikoshii [13, 33, 34], and PfTET3 from Pyrococcus furiosus [24]
Summary
The M42 aminopeptidases are dinuclear aminopeptidases displaying a peculiar tetrahedron-shaped structure with 12 subunits Their quaternary structure results from the self-assembly of six dimers controlled by their divalent metal ion cofactors. The metal ions have been described to bind the substrate, to facilitate nucleophile generation (water molecule deprotonation), and to stabilize the transition state of peptide hydrolysis [32] In addition to their catalytic roles, the metal ions could control the TET aminopeptidase oligomerization. Such a structural role has been reported for three M42 aminopeptidases, PhTET2 and PhTET3 from P. horikoshii [13, 33, 34], and PfTET3 from Pyrococcus furiosus [24]. Based on the current knowledge, we should avoid drawing general dogma on the TET aminopeptidases due to the lack of studies on metal ion binding behavior and structures in complex with substrates and inhibitors
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