Towards a comprehension of the structure of mouse proNGF
Francesca Paoletti, Sonia Covaceuszach, E. Schwarz, Milton T. Stubbs, Rainer Rudolph, Antonino Cattaneo, D. Lamba · Acta Crystallographica Section A Foundations of Crystallography · 2005
MACROMOLECULES C234translation initiation factor 2. The autoinhibited form of the GCN2 PK domain is activated in cells starved of amino acids by binding of uncharged tRNA to a histidyl-tRNA synthetase (HisRS)-like domain.Crystal structures of a GCN2 PK dimer have been determined for wild-type and mutant forms in the apo state and bound to ATP or AMPPNP.These structures reveal that autoinhibition results from stabilization of a closed bi-lobate conformation of the apo protein that restricts ATP binding.A hyperactive mutant form of the enzyme (R794G) shows a conformational change in the hinge region connecting the N-and C-lobes and significant intra-domain movement that enhances ATP binding and hydrolysis.We propose that interactions between the PK domain and the tRNA-bound form of the HisRS domain remodel the hinge region in a manner similar to the mechanism of enzyme activation by the R794G mutation.A hypothetical structural model of a PK 2 HisRS 2 tetramer places the kinase hinge near the PK-HisRS interface, poised for allosteric modulation following uncharged tRNA binding.