期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 32, 页码 13089-13094出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1105786108
关键词
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资金
- Offices of Biological and Environmental Research of the US Department of Energy
- Basic Energy Sciences of the US Department of Energy
- National Center for Research Resources (NCRR) of the National Institutes of Health (NIH) [P41RR012408]
- National Science Foundation (NSF)
- NIH/NIGMS under NSF [DMR-0225180]
- NIH through National Center for Research Resources [RR-01646]
- US Public Health Service [R01 DK21739, R01 GM-20194]
- National Heart, Lung and Blood Institute [5T32HL007594]
- American Heart Association [10PRE4200010]
Delivery of iron to cells requires binding of two iron-containing human transferrin (hTF) molecules to the specific homodimeric transferrin receptor (TFR) on the cell surface. Through receptor-mediated endocytosis involving lower pH, salt, and an unidentified chelator, iron is rapidly released from hTF within the endosome. The crystal structure of a monoferric N-lobe hTF/TFR complex (3.22-angstrom resolution) features two binding motifs in the N lobe and one in the C lobe of hTF. Binding of Fe(N)hTF induces global and site-specific conformational changes within the TFR ectodomain. Specifically, movements at the TFR dimer interface appear to prime the TFR to undergo pH-induced movements that alter the hTF/TFR interaction. Iron release from each lobe then occurs by distinctly different mechanisms: Binding of His349 to the TFR (strengthened by protonation at low pH) controls iron release from the C lobe, whereas displacement of one N-lobe binding motif, in concert with the action of the dilysine trigger, elicits iron release from the N lobe. One binding motif in each lobe remains attached to the same alpha-helix in the TFR throughout the endocytic cycle. Collectively, the structure elucidates how the TFR accelerates iron release from the C lobe, slows it from the N lobe, and stabilizes binding of apohTF for return to the cell surface. Importantly, this structure provides new targets for mutagenesis studies to further understand and define this system.
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