The C-terminal domain of Mnk1a plays a dual role in tightly regulating its activity.
The human family of MAPK (mitogen-activated protein kinase) signal-integrating kinases (Mnks) comprises four related proteins derived from two genes by alternative splicing. The MNK1 gene gives rise to two proteins, Mnk1a and Mnk1b, which possess distinct C-termini and properties. Despite lacking the C-terminal MAPK-binding site, Mnk1b shows higher basal activity than Mnk1a. In contrast, the activity of Mnk1a is tightly regulated by signalling through ERK (extracellular-signal-regulated kinase) and p38 MAPK. We show that the short C-terminus of Mnk1b confers on it a 'default' behaviour of substantial, but unregulated, activity. In contrast, the longer C-terminus of Mnk1a represses the basal activity and T (activation)-loop phosphorylation of this isoenzyme while allowing both properties to be stimulated by upstream MAPK signalling. Two features of the C-terminus of Mnk1a appear to account for this behaviour: the known MAPK-binding site and a region (predicted to be alpha-helical) which occludes access to the catalytic domain and the T-loop. The activation of Mnk1a results in a marked conformational change leading to a more 'open' structure. We also identified a conserved phenylalanine residue in an Mnk-specific insert as playing a key role in governing the ease with which Mnk1a can be phosphorylated. These studies help to identify the features that give rise to the diverse properties of human Mnk isoforms.
Goto
Susan
S
Department of Biochemistry and Molecular Biology and the Diabetes Research Group, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada.
Yao
Zhong
Z
Proud
Christopher G
CG
D000595:Amino Acid Sequence; D020134:Catalytic Domain / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D008969:Molecular Sequence Data; D010649:Phenylalanine / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013912:Threonine / Q000737:chemistry / Q000378:metabolism / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D013912:Threonine; D010649:Phenylalanine; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases