1fqe

From Proteopedia

Revision as of 13:48, 15 February 2008

CRYSTAL STRUCTURES OF MUTANT (K206A) THAT ABOLISH THE DILYSINE INTERACTION IN THE N-LOBE OF HUMAN TRANSFERRIN

Overview

Human transferrin (Tf) is responsible for the binding and transport of, iron in the bloodstream of vertebrates. Delivery of this bound iron to, cells occurs by a process of receptor-mediated endocytosis during which Tf, releases its iron at the reduced endosomal pH of approximately 5.6. Iron, release from Tf involves a large conformational change in which the two, domains that enclose the binding site in each lobe move apart. We have, examined the role of two lysines, Lys206 and Lys296, that form a, hydrogen-bonded pair close to the N-lobe binding site of human Tf and have, been proposed to form a pH-sensitive trigger for iron release. We report, high-resolution crystal structures for the K206A and K296A mutants of the, N-lobe half-molecule of Tf, hTf/2N, and quantitative iron release data on, these mutants and the double mutant K206A/K296A. The refined crystal, structures (for K206A, R = 19.6% and R(free) = 23.7%; for K296A, R= 21.2%, and R(free) = 29.5%) reveal a highly conserved hydrogen bonding network in, the dilysine pair region that appears to be maintained even when, individual hydrogen bonding groups change. The iron release data show that, the mutants retain iron to a pH 1 unit lower than the pH limit of wild, type hTf/2N, and release iron much more slowly as a result of the loss of, the dilysine interaction. Added chloride ions are shown to accelerate iron, release close to the pH at which iron is naturally lost and the closed, structure becomes destabilized, and to retard it at higher pH.

Disease

Known diseases associated with this structure: Atransferrinemia OMIM:[190000], Iron deficiency anemia, susceptibility to OMIM:[190000]

About this Structure

1FQE is a Single protein structure of sequence from Homo sapiens with , and as ligands. Full crystallographic information is available from OCA.

Reference

Crystal structures and iron release properties of mutants (K206A and K296A) that abolish the dilysine interaction in the N-lobe of human transferrin., Nurizzo D, Baker HM, He QY, MacGillivray RT, Mason AB, Woodworth RC, Baker EN, Biochemistry. 2001 Feb 13;40(6):1616-23. PMID:11327820

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