Intact intracellular tail is critical for proper functioning of the tumor-associated, hypoxia-regulated carbonic anhydrase IX.
Carbonic anhydrase IX (CA IX) is a tumor-associated, hypoxia-induced enzyme involved in pH regulation and cell adhesion. Its catalytically active ectodomain (ECD) is linked to a transmembrane region and a short intracellular (IC) tail. Removal of the IC tail causes intracellular localization of CA IX. Mutations of basic amino acids within IC do not perturb the membrane position, but reduce shedding of the CA IX ectodomain as well as CA IX-mediated cell dissociation. Moreover, they abolish the CA IX capacity to acidify extracellular pH (pHe) and bind CA IX-selective sulfonamide inhibitor in hypoxia. These findings provide the first evidence for the critical contribution of the IC tail to the proper functioning of CA IX.
Hulikova
Alzbeta
A
Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovak Republic.
Zatovicova
Miriam
M
Svastova
Eliska
E
Ditte
Peter
P
Brasseur
Robert
R
Kettmann
Richard
R
Supuran
Claudiu T
CT
Kopacek
Juraj
J
Pastorek
Jaromir
J
Pastorekova
Silvia
S
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015151:Immunoblotting; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D011485:Protein Binding; D055503:Protein Multimerization; D017386:Sequence Homology, Amino Acid
D000951:Antigens, Neoplasm; D008565:Membrane Proteins; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases