Structure of Human NatA and Its Regulation by the Huntingtin Interacting Protein HYPK.

Co-translational N-terminal protein acetylation regulates many protein functions including degradation, folding, interprotein interactions, and targeting. Human NatA (hNatA), one of six conserved metazoan N-terminal acetyltransferases, contains Naa10 catalytic and Naa15 auxiliary subunits, and associates with the intrinsically disordered Huntingtin yeast two-hybrid protein K (HYPK). We report on the crystal structures ...
of hNatA and hNatA/HYPK, and associated biochemical and enzymatic analyses. We demonstrate that hNatA contains unique features: a stabilizing inositol hexaphosphate (IP6) molecule and a metazoan-specific Naa15 domain that mediates high-affinity HYPK binding. We find that HYPK harbors intrinsic hNatA-specific inhibitory activity through a bipartite structure: a ubiquitin-associated domain that binds a hNaa15 metazoan-specific region and an N-terminal loop-helix region that distorts the hNaa10 active site. We show that HYPK binding blocks hNaa50 targeting to hNatA, likely limiting Naa50 ribosome localization in vivo. These studies provide a model for metazoan NAT activity and HYPK regulation of N-terminal acetylation.
Mesh Terms:
Acetylation, Animals, Binding Sites, Carrier Proteins, Crystallography, X-Ray, Gene Expression Regulation, Humans, Models, Molecular, N-Terminal Acetyltransferase A, N-Terminal Acetyltransferase E, Protein Binding, Protein Conformation, Protein Stability, Sf9 Cells, Species Specificity
Structure
Date: Jul. 03, 2018
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