Molecular modeling of human serum transferrin for rationalizing the changes in its physicochemical properties induced by iron binding. Implication of the mechanism of binding to its receptor.
In order to rationalize the physicochemical properties of human serum-transferrin (STf) and the STf-receptor (TfR) recognition process, we have tried to predict the 3D structures of apo- and iron-loaded STf using a homology modeling technique to study the changes in the structural characteristics that take place upon the uptake of iron by STf in solution. The crystal structures of both forms for ovotransferrin were used as templates for the STf modeling. The modeled structure of STf gave a satisfactory interpretation for the typical physicochemical properties such that (1) STf has a negative electrophoretic mobility and its value increases with iron uptake, and (2) the radius of gyration Rg of Tf decreases with iron uptake. It was found that upon iron binding, interdomain closures take place with large movements of the NII and CII subdomains comprising the N- and C-lobes in STf through a hinge-bending motion, accompanied by the opening of the bridge region with a displacement of more than 15 A. Moreover, in view of the findings from our capillary electrophoresis experiments that the electrostatic interactions significantly contribute to a specific binding of Fe2-STf with TfR, it is inferred that the connecting (bridge) and its neighboring region associated with a surface exposure of negative charge play an important role in the STf-receptor recognition process.
Yajima
H
H
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Japan. hyajima@ch.kagu.sut.ac.jp
Sakajiri
T
T
Kikuchi
T
T
Morita
M
M
Ishii
T
T
D000595:Amino Acid Sequence; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003207:Conalbumin / Q000235:genetics; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011990:Receptors, Transferrin / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D014168:Transferrin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D011990:Receptors, Transferrin; D014168:Transferrin; D003207:Conalbumin; D007501:Iron