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Title: The Crystal Structure of Iron-free Human Serum Transferrin Provides Insight into Inter-lobe Communication and Receptor Binding

Abstract

Serum transferrin reversibly binds iron in each of two lobes and delivers it to cells by a receptor-mediated, pH-dependant process. The binding and release of iron results in a large conformational change in which two subdomains in each lobe close or open with a rigid twisting motion around a hinge. We report the structure of human serum transferrin (hTF) lacking iron (apo-hTF) which was independently determined by two methods: (1) the crystal structure of recombinant non-glycosylated apo-hTF was solved at 2.7 Angstroms resolution using a MAD phasing strategy, by substituting the nine methionines in hTF with selenomethionine and (2) the structure of glycosylated apo-hTF (isolated from serum) was determined to a resolution of 2.7 Angstroms by molecular replacement using the human apo-N-lobe and the rabbit holo-C1-subdomain as search models. These two crystal structures are essentially identical. They represent the first published model for full-length human TF and reveal that, in contrast to family members (human lactoferrin and hen ovotransferrin), both lobes are almost equally open: 59.4 deg and 49.5 deg rotations are required to open the N- and C-lobe, respectively, (compared to closed pig TF). Availability of this structure is critical to a complete understanding of the metal binding propertiesmore » of each lobe of hTF; the apo-hTF structure suggests that differences in the hinge regions of the N- and C-lobes may influence the rates of iron binding and release. In addition, we evaluate potential interactions between apo-hTF and the human transferrin receptor.« less

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
914319
Report Number(s):
BNL-78887-2007-JA
Journal ID: ISSN 0021-9258; JBCHA3; TRN: US200809%%174
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Biol. Chem.; Journal Volume: 281; Journal Issue: 34
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; AVAILABILITY; COMMUNICATIONS; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; IRON; LACTOFERRIN; RABBITS; RESOLUTION; TRANSFERRIN; national synchrotron light source

Citation Formats

Wally,J., Halbrooks, P., Vonrhein, C., Rould, M., Everse, S., Mason, A., and Buchanan, S.. The Crystal Structure of Iron-free Human Serum Transferrin Provides Insight into Inter-lobe Communication and Receptor Binding. United States: N. p., 2006. Web. doi:10.1074/jbc.M604592200.
Wally,J., Halbrooks, P., Vonrhein, C., Rould, M., Everse, S., Mason, A., & Buchanan, S.. The Crystal Structure of Iron-free Human Serum Transferrin Provides Insight into Inter-lobe Communication and Receptor Binding. United States. doi:10.1074/jbc.M604592200.
Wally,J., Halbrooks, P., Vonrhein, C., Rould, M., Everse, S., Mason, A., and Buchanan, S.. Sun . "The Crystal Structure of Iron-free Human Serum Transferrin Provides Insight into Inter-lobe Communication and Receptor Binding". United States. doi:10.1074/jbc.M604592200.
@article{osti_914319,
title = {The Crystal Structure of Iron-free Human Serum Transferrin Provides Insight into Inter-lobe Communication and Receptor Binding},
author = {Wally,J. and Halbrooks, P. and Vonrhein, C. and Rould, M. and Everse, S. and Mason, A. and Buchanan, S.},
abstractNote = {Serum transferrin reversibly binds iron in each of two lobes and delivers it to cells by a receptor-mediated, pH-dependant process. The binding and release of iron results in a large conformational change in which two subdomains in each lobe close or open with a rigid twisting motion around a hinge. We report the structure of human serum transferrin (hTF) lacking iron (apo-hTF) which was independently determined by two methods: (1) the crystal structure of recombinant non-glycosylated apo-hTF was solved at 2.7 Angstroms resolution using a MAD phasing strategy, by substituting the nine methionines in hTF with selenomethionine and (2) the structure of glycosylated apo-hTF (isolated from serum) was determined to a resolution of 2.7 Angstroms by molecular replacement using the human apo-N-lobe and the rabbit holo-C1-subdomain as search models. These two crystal structures are essentially identical. They represent the first published model for full-length human TF and reveal that, in contrast to family members (human lactoferrin and hen ovotransferrin), both lobes are almost equally open: 59.4 deg and 49.5 deg rotations are required to open the N- and C-lobe, respectively, (compared to closed pig TF). Availability of this structure is critical to a complete understanding of the metal binding properties of each lobe of hTF; the apo-hTF structure suggests that differences in the hinge regions of the N- and C-lobes may influence the rates of iron binding and release. In addition, we evaluate potential interactions between apo-hTF and the human transferrin receptor.},
doi = {10.1074/jbc.M604592200},
journal = {J. Biol. Chem.},
number = 34,
volume = 281,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 2006},
month = {Sun Jan 01 00:00:00 EST 2006}
}