Biomedical subjects

S Faham

Publications and source records attributed to S Faham.

7 recordsLinked to original sources

PubMed2001

Polymerization of the SAM domain of TEL in leukemogenesis and transcriptional repression.

TEL is a transcriptional repressor that is a frequent target of chromosomal translocations in a large number of hematalogical malignancies. These rearrangements fuse a potent oligomerization module, the SAM domain of TEL, to a variety of tyrosine kinases or transcriptional regulatory proteins. The self-associating property of TEL-SAM is essential for cell transformation in many, if not all of these diseases. Here we show that the TEL-SAM domain forms a helical, head-to-tail polymeric structure held together by strong intermolecular contacts, providing the first clear demonstration that SAM domains can polymerize. Our results also suggest a mechanism by which SAM domains could mediate the spreading of transcriptional repression complexes along the chromosome.

Amino Acid Sequence↗

PubMed1999

Monomeric structure of the human EphB2 sterile alpha motif domain.

The sterile alpha motif (SAM) domain is a protein module found in many diverse signaling proteins. SAM domains in some systems have been shown to self-associate. Previous crystal structures of an EphA4-SAM domain dimer (Stapleton, D., Balan, I., Pawson, T., and Sicheri, F. (1999) Nat. Struct. Biol. 6, 44-49) and a possible EphB2-SAM oligomer (Thanos, C. D., Goodwill, K. E., and Bowie, J. U. (1999) Science 283, 833-836) both revealed large interfaces comprising an exchange of N-terminal peptide arms. Within the arm, a conserved hydrophobic residue (Tyr-8 in the EphB2-SAM structure or Phe-910 in the EphA4-SAM structure) is anchored into a hydrophobic cleft on a neighboring molecule. Here we have solved a new crystal form of the human EphB2-SAM domain that has the same overall SAM domain fold yet has no substantial intermolecular contacts. In the new structure, the N-terminal peptide arm of the EphB2-SAM domain protrudes out from the core of the molecule, leaving both the arm (including Tyr-8) and the hydrophobic cleft solvent-exposed. To verify that Tyr-8 is solvent-exposed in solution, we made a Tyr-8 to Ala-8 mutation and found that the EphB2-SAM domain structure and stability were only slightly altered. These results suggest that Tyr-8 is not part of the hydrophobic core of the EphB2-SAM domain and is conserved for functional reasons. Cystallographic evidence suggests a possible role for the N-terminal arm in oligomerization. In the absence of a direct demonstration of biological relevance, however, the functional role of the N-terminal arm remains an open question.

Amino Acid Motifs↗

PubMed1999

Formaldehyde ferredoxin oxidoreductase from Pyrococcus furiosus: the 1.85 A resolution crystal structure and its mechanistic implications.

Crystal structures of formaldehyde ferredoxin oxidoreductase (FOR), a tungstopterin-containing protein from the hyperthermophilic archaeon Pyrococcus furiosus, have been determined in the native state and as a complex with the inhibitor glutarate at 1.85 A and 2. 4 A resolution, respectively. The native structure was solved by molecular replacement using the structure of the homologous P. furiosus aldehyde ferredoxin oxidoreductase (AOR) as the initial model. Residues are identified in FOR that may be involved in either the catalytic mechanism or in determining substrate specificity. The binding site on FOR for the physiological electron acceptor, P. furiosus ferredoxin (Fd), has been established from an FOR-Fd cocrystal structure. Based on the arrangement of redox centers in this structure, an electron transfer pathway is proposed that begins at the tungsten center, leads to the (4Fe:4S) cluster of FOR via one of the two pterins that coordinate the tungsten, and ends at the (4Fe:4S) cluster of ferredoxin. This pathway includes two residues that coordinate the (4Fe:4S) clusters, Cys287 of FOR and Asp14 of ferredoxin. Similarities in the active site structures between FOR and the unrelated molybdoenzyme aldehyde oxidoreductase from Desulfovibrio gigas suggest that both enzymes utilize a common mechanism for aldehyde oxidation.

Aldehyde Oxidoreductases↗

PubMed1999

Structures of ruthenium-modified Pseudomonas aeruginosa azurin and [Ru(2,2'-bipyridine)2(imidazole)2]SO4 x 10H2O.

The crystal structure of Ru(2, 2'-bipyridine)2(imidazole)(His83)azurin (RuAz) has been determined to 2.3 A -resolution by X-ray crystallography. The spectroscopic and thermodynamic properties of both the native protein and [Ru(2, 2'-bipyridine)2(imidazole)2]2+ are maintained in the modified protein. Dark-green RuAz crystals grown from PEG 4000, LiNO3, CuCl2 and Tris buffer are monoclinic, belong to the space group C2 and have cell parameters a = 100.6, b = 35.4, c = 74.7 A and beta = 106. 5 degrees. In addition, [Ru(2,2'-bipyridine)2(imidazole)2]SO4 x 10H2O was synthesized, crystallized and structurally characterized by X-ray crystallography. Red-brown crystals of this complex are monoclinic, space group P21/n, unit-cell parameters a = 13.230 (2), b = 18.197 (4), c = 16.126 (4) A, beta = 108.65 (2) degrees. Stereochemical parameters for the refinement of Ru(2, 2'-bipyridine)2(imidazole)(His83) were taken from the atomic coordinates of [Ru(2,2'-bipyridine)2(imidazole)2]2+. The structure of RuAz confirms that His83 is the only site of chemical modification and that the native azurin structure is not perturbed significantly by the ruthenium label.

Azurin↗

PubMed1998

Diversity does make a difference: fibroblast growth factor-heparin interactions.

Fibroblast growth factors (FGFs) are members of a protein family with a broad range of biological activities. The best characterized FGFs interact with two distinct extracellular receptors--a transmembrane tyrosine kinase FGF receptor (FGFR) and a heparan f1p4ate-related proteoglycan of the extracellular matrix. These components form a FGF-FGFR-proteoglycan complex that activates the FGF-mediated signal transduction process through FGFR dimerization. Recent crystal structure determinations of FGF-heparin complexes have provided insights into both the interactions between these components and the role of heparin-like proteoglycans in FGF function. Future advances in this field will benefit enormously from an ability to specifically prepare homogeneous heparin-based oligosaccharides of defined sequence for use in biochemical and structural studies of FGF and many other systems.

Binding Sites↗

PubMed1996

Heparin structure and interactions with basic fibroblast growth factor.

Crystal structures of heparin-derived tetra- and hexasaccharides complexed with basic fibroblast growth factor (bFGF) were determined at resolutions of 1.9 and 2.2 angstroms, respectively. The heparin structure may be approximated as a helical polymer with a disaccharide rotation of 174 degrees and a translation of 8.6 angstroms along the helix axis. Both molecules bound similarly to a region of the bFGF surface containing residues asparagine-28, arginine-121, lysine-126, and glutamine-135, the hexasaccharide also interacted with an additional binding site formed by lysine-27, asparagine-102, and lysine-136. No significant conformational change in bFGF occurred upon heparin oligosaccharide binding, which suggests that heparin primarily serves to juxtapose components of the FGF signal transduction pathway.

Binding Sites↗

PubMed1991

Three-dimensional structures of acidic and basic fibroblast growth factors.

Members of the fibroblast growth factor (FGF) family of proteins stimulate the proliferation and differentiation of a variety of cell types through receptor-mediated pathways. The three-dimensional structures of two members of this family, bovine acidic FGF and human basic FGF, have been crystallographically determined. These structures contain 12 antiparallel beta strands organized into a folding pattern with approximate threefold internal symmetry. Topologically equivalent folds have been previously observed for soybean trypsin inhibitor and interleukins-1 beta and -1 alpha. The locations of sequences implicated in receptor and heparin binding by FGF are presented. These sites include beta-sheet strand 10, which is adjacent to the site of an extended sequence insertion in several oncogene proteins of the FGF family, and which shows sequence conservation among the FGF family and interleukin-1 beta.

Amino Acid Sequence↗