Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells
Da. Whittington et al., Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells, P NAS US, 98(17), 2001, pp. 9545-9550
Citations number
63
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Overexpression of the zinc enzyme carbonic anhydrase (CA: EC 4.2.1.1) XII i
s observed in certain human cancers. This bitopic membrane protein contains
an N-terminal extracellular catalytic domain, a membrane-spanning a-helix,
and a small intracellular C-terminal domain. We have determined the three-
dimensional structure of the extracellular catalytic domain of human CA XII
by x-ray crystallographic methods at 1.55-Angstrom resolution. The structu
re reveals a prototypical CA fold; however, two CA XII domains associate to
form an isologous dimer, an observation that is confirmed by studies of th
e enzyme in solution. The identification of signature GXXXG and GXXXS motif
s in the transmembrane sequence that facilitate helix-helix association is
additionally consistent with dimeric architecture. The dimer interface is s
ituated so that the active site clefts of each monomer are clearly exposed
on one face of the dimer, and the C-termini are located together on the opp
osite face of the dimer to facilitate membrane interaction. The amino acid
composition of the active-site cleft closely resembles that of the other CA
isozymes in the immediate vicinity of the catalytic zinc ion, but differs
in the region of the nearby a-helical "130's segment." The structure of the
CA Xii-acetazolamide complex is also reported at 1.50-Angstrom resolution,
and prospects for the design of CA XII-specific inhibitors of possible che
motherapeutic value are discussed.