Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.2.13 (aldolase)
 3,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A structural basis for activation and substrate specificity of src tyrosine kinases, and regulation of protein-protein association by tyrosine phosphorylation is described. Lyn, a src-family tyrosine kinase, recognizes and phosphorylates the immunoreceptor tyrosine-based activation motif, ITAM, a critical component in transmembrane signal transduction in hemopoietic cells. The structure of an ITAM peptide substrate bound to an active form of Lyn tyrosine kinase was determined by high-resolution NMR, and a model of the complex was generated using the crystallographic structure of Lck, a closely related Src-family kinase. The results provide a rationale for the conserved ITAM residues and specificity of Lyn, and suggest that substrate plays a role in stabilizing the kinase conformation optimal for catalysis. It is our hope that the Lck-ITAM peptide model complex will be useful in aiding structure-based drug design efforts that target substrate binding determinants in the design. Concerning the regulation of protein-protein association, we report on a complex between erythrocyte band 3 and two glycolytic enzymes, aldolase and glyceraldehyde-3-phosphate dehydrogenase. The formation of this complex is negatively regulated by tyrosine phosphorylation of band 3 by p72syk tyrosine kinase. In red blood cells, this association results in a decrease in glycolysis due to competitive inhibition of the glycolytic enzymes. The structure of band 3 recognized by the glycolytic enzymes was determined by solution NMR, and found to be a loop structure with tyrosine centrally positioned and excluded from intermolecular contact. This phosphorylation sensitive interaction, or PSI, loop may be the basis of a general mechanism for negative regulation through tyrosine phosphorylation.
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PMID:NMR structure of phospho-tyrosine signaling complexes. 1039 26

The red blood cell membrane (RBCM) is a primary model for animal cell plasma membranes. One of its major organizing centers is the cytoplasmic domain of band 3 (cdb3), which links multiple proteins to the membrane. Included among its peripheral protein ligands are ankyrin (the major bridge to the spectrin-actin skeleton), protein 4. 1, protein 4.2, aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphofructokinase, deoxyhemoglobin, p72syk protein tyrosine kinase, and hemichromes. The crystal structure of cdb3 is reported at 0.26 nm (2.6 A) resolution. A tight symmetric dimer is formed by cdb3; it is stabilized by interlocked dimerization arms contributed by both monomers. Each subunit also includes a larger peripheral protein binding domain with an alpha(+) beta-fold. The binding sites of several peripheral proteins are localized in the structure, and the nature of the major conformational change that regulates membrane-skeletal interactions is evaluated. An improved structural definition of the protein network at the inner surface of the RBCM is now possible.
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PMID:Crystallographic structure and functional interpretation of the cytoplasmic domain of erythrocyte membrane band 3. 1104 68

The N-terminal cytoplasmic domain of the anion exchanger 1 (AE1 or band 3) of the human erythrocyte associates with peripheral membrane proteins to regulate membrane-cytoskeleton interactions, with glycolytic enzymes such as glyceraldehyde-3-phosphate dehydrogenase and aldolase, with the protein-tyrosine kinase p72syk, with hemoglobin and with hemichromes. We have demonstrated that the N-terminal cytoplasmic domain of band 3 (CDB3) is a substrate of the apoptosis executioner caspase 3 (1). CDB3 has two non-conventional caspase 3 cleavage sites, TATD45 and EQGD205 (2). In vitro treatment of recombinant CDB3 with caspase 3 generated two fragments, which could be blocked by pretreatment with the caspase 3 inhibitor Z-DEVD-fmk (3). Recombinant CDB3 in which the caspase 3 cleavage sites Asp45 and Asp205 were mutated, was resistant to proteolysis (4). Proteolytically derived fragments crossreactive with polyclonal anti-band 3 antibody appeared with simultaneous cleavage of poly (ADP-ribose) polymerase and procaspase 3 in staurosporine (STS)-treated HEK293 cells transiently transfected with CDB3 (5). In vivo cleavage of CDB3 could be blocked by pretreatment of cells with Z-DEVD-fmk or in cells transfected with mutant CDB3 (D45A, D205A) (6). Co-transfection experiments showed that STS-mediated cleavage of CDB3 diminished its interaction with the N-terminal domain of protein 4.2, confirming that such cleavage interferes with the interaction of CDB3 with cytoskeletal proteins (7). Active caspase 3 was observed in aged red cells but not in young cells. This red cell caspase 3 could cleave band 3 present in inside-out vesicles prepared from young erythrocytes arguing in favor of a physiological role of caspase 3 in aged erythrocytes.
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PMID:Caspase 3-mediated proteolysis of the N-terminal cytoplasmic domain of the human erythroid anion exchanger 1 (band 3). 1457 Sep 14