2o7u
From Proteopedia
Crystal structure of K206E/K296E mutant of the N-terminal half molecule of human transferrin
Structural highlights
Disease[TRFE_HUMAN] Defects in TF are the cause of atransferrinemia (ATRAF) [MIM:209300]. Atransferrinemia is rare autosomal recessive disorder characterized by iron overload and hypochromic anemia.[1] [2] Function[TRFE_HUMAN] Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate. It is responsible for the transport of iron from sites of absorption and heme degradation to those of storage and utilization. Serum transferrin may also have a further role in stimulating cell proliferation. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedIron uptake by humans depends on the ability of the serum protein transferrin (Tf) to bind iron as Fe(3+) with high affinity but reversibly. Iron release into cells occurs through receptor-mediated endocytosis, aided by the lower endosomal pH of about 5.5. The protonation of a hydrogen-bonded pair of lysines, Lys206 and Lys296, adjacent to the N-lobe iron site of Tf has been proposed to create a repulsive interaction that stimulates domain opening and iron release. The crystal structures of two mutants, K206E (in which Lys206 is mutated to Glu) and K206E/K296E (in which both lysines are mutated to Glu), have been determined. The K206E structure (2.6 A resolution; R = 0.213, R(free) = 0.269) shows that a salt bridge is formed between Glu206 and Lys296, thus explaining the drastically slower iron release by this mutant. The K206E/K296E double-mutant structure (2.8 A resolution; R = 0.232, R(free) = 0.259) shows that the Glu296 side chain moves away from Glu206, easing any repulsive interaction and instead interacting with the iron ligand His249. The evident conformational flexibility is consistent with an alternative model for the operation of the dilysine pair in iron release in which it facilitates concerted proton transfer to the tyrosine ligand Tyr188 as one step in the weakening of iron binding. Structures of two mutants that probe the role in iron release of the dilysine pair in the N-lobe of human transferrin.,Baker HM, Nurizzo D, Mason AB, Baker EN Acta Crystallogr D Biol Crystallogr. 2007 Mar;63(Pt 3):408-14. Epub 2007, Feb 21. PMID:17327678[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
