IRON DELIVERY VIA BLOOD--STRUCTURAL ROLE OF TRANSFERRIN

University Of Vermont &St Agric College, Burlington VT

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Abstract

DESCRIPTION: (applicant's abstract) This proposal involves the elucidation of structure-function relationships in recombinant transferrins, e.g., human transferrin, hen ovo-transferrin and half-molecules thereof, based on a series of site directed mutants. A major aim will be to establish by a series of physico-chemical approaches, such as NMR, fluorescence resonance energy transfer, and EPR of spin-labeled proteins, reliable indices of the "open" and "closed" conformations. These measurements will be undertaken as a function of pH, ionic strength, and degree of metal ligation. Metal binding affinities will be correlated with the conformational states of the proteins and various mutants. The principal criterion for metal binding affinity will be kinetic constants for the release of the bound metal ion to a competing high affinity chelator. X-ray crystallographic studies of various mutants will be continued in order to determine any marked effects in the structure of the protein arising from the mutants. Iron sequestration in blood plasma by transferrin and delivery of this iron via receptor mediated endocytosis to various tissues are biologically essential functions. This natural physiological process is also utilized in the supply of essential iron to neoplastic tissues. The fundamentals of structure-function relationships in transferrin are essential to understanding the molecular basis of certain defects in iron delivery and to the design of rational interventions in the delivery of iron to neoplasms.