3btb

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NMR SOLUTION STRUCTURE OF A BAND 3 PEPTIDE INHIBITOR BOUND TO GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE, 20 STRUCTURES

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

A protein-protein association regulated by phosphorylation of tyrosine is, examined by NMR structural studies and biochemical studies. Binding of, glyceraldehyde-3-phosphate dehydrogenase (G3PDH) and aldolase to the, N-terminus of human erythrocyte anion transporter, band 3, inhibits enzyme, activity. This inhibition is reversed upon phosphorylation of band 3 Y8, as shown by kinetic studies on purified components, as well as in vivo, studies. Thus, tyrosine phosphorylation mediates against the, intermolecular protein-protein association, in contrast to the positive, control involving SH2 and PTB domains where phosphorylation is required, for binding. To elucidate the basis of recognition and negative control by, tyrosine phosphorylation, the structure of a synthetic peptide, B3P, corresponding to the first 15 residues of band 3 (MEELQDDYEDMMEEN-NH2), bound to G3PDH has been determined using the exchange-transferred nuclear, Overhauser effect. The G3PDH-bound B3P structure was found to be very, similar to the structure recognized by aldolase. A hydrophobic triad forms, from side chains within a loop structure of residues 4 through 9 in both, bound species. Another structural feature stabilizing the loop, in the, case of the B3P-G3PDH complex, is a hydrogen bond between the side chains, of Y8 and D10 associated with a beta-turn of residues 8-11. Based on the, structure of this phosphorylation sensitive interaction (PSI) loop, it is, suggested that tyrosine phosphorylation disrupts protein-protein, association, in part, by intramolecular electrostatic destabilization. The, inhibition by B3P is competitive with respect to the coenzyme NAD+ and, noncompetitive with the substrate analog arsenate. Specific binding of B3P, to G3PDH is demonstrated by reversion of the NMR spectral properties of, bound B3P to those of the free peptide upon addition of coenzyme and, substrate analog. The stoichiometry of binding for the B3P-G3PDH complex, was determined from Sephadex G-50 displacement experiments to be 4:1., Collectively, these results are consistent with B3P binding the active, site of G3PDH.

Disease

Known diseases associated with this structure: Acanthocytosis, one form OMIM:[109270], Blood group, Diego OMIM:[109270], Blood group, Waldner OMIM:[109270], Blood group, Wright OMIM:[109270], Diabetes insipidus, nephrogenic OMIM:[300538], Elliptocytosis, Malaysian-Melanesian type OMIM:[109270], Hemolytic anemia due to band 3 defect defect OMIM:[109270], Nephrogenic syndrome of inappropriate antidiuresis OMIM:[300538], OMIM:[[1]]109270, Renal tubular acidosis, distal, 179800 OMIM:[109270], Spherocytosis, hereditary OMIM:[109270]

About this Structure

3BTB is a Single protein structure of sequence from Homo sapiens with NH2 as ligand. Full crystallographic information is available from OCA.

Reference

Insights into tyrosine phosphorylation control of protein-protein association from the NMR structure of a band 3 peptide inhibitor bound to glyceraldehyde-3-phosphate dehydrogenase., Eisenmesser EZ, Post CB, Biochemistry. 1998 Jan 20;37(3):867-77. PMID:9454576

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