Structure of Pyruvate Dehydrogenase Kinase: NOVEL FOLDING PATTERN FOR A SERINE PROTEIN KINASE

R B Sloan,C N Steussy,K M Popov,M M Bowker-Kinley,R A Harris,J A Hamilton

doi:10.1074/jbc.m104285200

Abstract

The structure of mitochondrial pyruvate dehydrogenase kinase isozyme 2 is of interest because it represents a family of serine-specific protein kinases that lack sequence similarity with all other eukaryotic protein kinases. Similarity exists instead with key motifs of prokaryotic histidine protein kinases and a family of eukaryotic ATPases. The 2.5-A crystal structure reported here reveals that pyruvate dehydrogenase kinase isozyme 2 has two domains of about the same size. The N-terminal half is dominated by a bundle of four amphipathic alpha-helices, whereas the C-terminal half is folded into an alpha/beta sandwich that contains the nucleotide-binding site. Analysis of the structure reveals this C-terminal domain to be very similar to the nucleotide-binding domain of bacterial histidine kinases, but the catalytic mechanism appears similar to that of the eukaryotic serine kinases and ATPases.

Highlights

The structure of mitochondrial pyruvate dehydrogenase kinase isozyme 2 is of interest because it represents a family of serine-specific protein kinases that lack sequence similarity with all other eukaryotic protein kinases
In contrast to the ATPases, an alignment of multiple histidine kinases to the PDK2 model shows that the position of the general base Glu-243 of PDK2 is occupied by a variety of residues and the positive charge contributed by Lys-246 in PDK2 is entirely absent
Variations of particular amino acids over time have allowed this domain to be adapted to three different biochemical roles: ATPase, histidine kinase, and serine kinase

Summary

Introduction

The structure of mitochondrial pyruvate dehydrogenase kinase isozyme 2 is of interest because it represents a family of serine-specific protein kinases that lack sequence similarity with all other eukaryotic protein kinases. Pyruvate dehydrogenase kinase (PDK) binds to the lipoyl domain, where it monitors changes in the reduced and acetylated states of the lipoic acid ligand and adjusts its activity . The C-terminal nucleotide-binding domain is folded as a mixed ␣/␤ structure (Fig. 1, a, b, and d).

Results

Conclusion