PB1 domain-mediated heterodimerization in NADPH oxidase and signaling complexes of atypical protein kinase C with Par6 and p62.
Maximal activation of NADPH oxidase requires formation of a complex between the p40(phox) and p67(phox) subunits via association of their PB1 domains. We have determined the crystal structure of the p40(phox)/p67(phox) PB1 heterodimer, which reveals that both domains have a beta grasp topology and that they bind in a front-to-back arrangement through conserved electrostatic interactions between an acidic OPCA motif on p40(phox) and basic residues in p67(phox). The structure enabled us to identify residues critical for heterodimerization among other members of the PB1 domain family, including the atypical protein kinase C zeta (PKC zeta) and its partners Par6 and p62 (ZIP, sequestosome). Both Par6 and p62 use their basic "back" to interact with the OPCA motif on the "front" of the PKC zeta. Besides heterodimeric interactions, some PB1 domains, like the p62 PB1, can make homotypic front-to-back arrays.
Wilson
Michael I
MI
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom.
Gill
David J
DJ
Perisic
Olga
O
Quinn
Mark T
MT
Williams
Roger L
RL
D000595:Amino Acid Sequence / Q000502:physiology; D001665:Binding Sites / Q000502:physiology; D019281:Dimerization; D006360:Heat-Shock Proteins / Q000378:metabolism*; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019255:NADPH Oxidases / Q000378:metabolism*; D010587:Phagocytosis / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D011506:Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology
D006360:Heat-Shock Proteins; D046911:Macromolecular Substances; D010750:Phosphoproteins; D011506:Proteins; C085072:neutrophil cytosol factor 40K; C079789:neutrophil cytosol factor 67K; D019255:NADPH Oxidases; C115015:PKC-3 protein; D011493:Protein Kinase C