Dynamic and structural characterization of a bacterial FHA protein reveals a new autoinhibition mechanism.
The OdhI protein is key regulator of the TCA cycle in Corynebacterium glutamicum. This highly conserved protein is found in GC rich Gram-positive bacteria (e.g., the pathogenic Mycobacterium tuberculosis). The unphosphorylated form of OdhI inhibits the OdhA protein, a key enzyme of the TCA cycle, whereas the phosphorylated form is inactive. OdhI is predicted to be mainly a single FHA domain, a module that mediates protein-protein interaction through binding of phosphothreonine peptides, with a disordered N-terminal extension substrate of the serine/threonine protein kinases. In this study, we solved the solution structure of the unphosphorylated and phosphorylated isoforms of the protein. We observed a major conformational change between the two forms characterized by the binding of the phosphorylated N-terminal part of the protein to its own FHA domain, consequently inhibiting it. This structural observation corresponds to a new autoinhibition mechanism described for a FHA domain protein.
Centre National de la Recherche Scientifique Unité Mixte de Recherche, Montpellier, France.
Philippe
P
Barthe
Christian
C
Roumestand
Marc J
MJ
Canova
Laurent
L
Kremer
Corinne
C
Hurard
Virginie
V
Molle
Martin
M
Cohen-Gonsaud
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D048230:Corynebacterium glutamicum / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D010769:Phosphothreonine / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity / Q000235:genetics
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D010455:Peptides; D010769:Phosphothreonine; D007655:Ketoglutarate Dehydrogenase Complex; D017346:Protein Serine-Threonine Kinases