Heterodimerize

Figure 9.12 Schematic diagram of the structure of the heterodimeric yeast transcription factor Mat a2-Mat al bound to DNA. Both Mat o2 and Mat al are homeodomains containing the helix-turn-helix motif. The first helix in this motif is colored blue and the second, the recognition helix, is red. (a) The assumed structure of the Mat al homeodomain in the absence of DNA, based on Its sequence similarity to other homeodomains of known structure, (b) The structure of the Mat o2 homeodomain. The C-terminal tail (dotted) is flexible in the monomer and has no defined structure, (c) The structure of the Mat a 1-Mat a2-DNA complex. The C-terminal domain of Mat a2 (yellow) folds into an a helix (4) in the complex and interacts with the first two helices of Mat a2, to form a heterodimer that binds to DNA. (Adapted from B.J. Andrews and M.S. Donoviel, Science 270 251-253, 1995.)...

How is the binding specificity of the heterodimer achieved compared with the specificity of Mat a2 alone The crystal structure rules out the simple model that the contacts made between the Mat a2 homeodomain and DNA are altered as a result of heterodimerization. The contacts between the Mat o2 homeodomain and DNA in the heterodimer complex are virtually indistinguishable from those seen in the structure of the Mat o2 monomer bound to DNA. However, there are at least two significant factors that may account for the increased specificity of the heterodimer. First, the Mat al homeodomain makes significant contacts with the DNA, and the heterodimeric complex will therefore bind more tightly to sites that provide the contacts required by both partners. Second, site-directed mutagenesis experiments have shown that the protein-protein interactions involving the... 

Figure 10.19 Heterodimerization of leucine zipper proteins can alter their DNA-binding specificity. Leucine zipper homodimers bind to symmetric DNA sequences, as shown In the left-hand and center drawings. These two proteins recognize different DNA sequences, as indicated by the red and blue regions in the DNA. The two different monomers can combine to form a heterodimer that recognizes a hybrid DNA sequence, composed of one red and one blue region.

Dimerization of the Ce-zinc cluster transcription factors involves an a-helical coiled coil in the dimerization region. Coiled coils, often called leucine zippers, are also found in a large group of transcription factors that do not contain zinc. The leucine zipper is made up of two a helices in a coiled coil with every seventh residue leucine or some other large hydrophobic residue, such as isoleucine or valine. Leucine zipper transcription factors (b/zip) include factors characterized by heterodimerization, for example Fos and Jun. The a-helical DNA-binding motifs of the heterodimers recognize quite different base sequences and are continous with the a helices of the zipper. 

The structure of the LH2 complex of R. acidophila is both simple and elegant (Figure 12.17). It is a ring of nine identical units, each containing an a and a P polypeptide of 53 and 41 residues, respectively, which both span the membrane once as a helices (Figure 12.18). The two polypeptides bind a total of three chlorophyll molecules and two carotenoids. The nine heterodimeric units form a hollow cylinder with the a chains forming the inner wall and the P chains the outer wall. The hole in the middle of the cylinder is empty, except for lipid molecules from the membrane. 

T-cell receptors (TCR) are heterodimeric transmembrane glycoproteins found exclusively in T cells, with extracellular domains that closely resemble antibody Fab structures. Each of the TCR a and p chains forms half of an extracellular antigen-binding domain, and in addition has one transmembrane... 

Interestingly, Gassman and co-workers have demonstrated that the regulation of the induction of AHR by indolo[3,2-/)]carbazole (4) was reduced by prior activation of the hypoxia-inducible expression. As the hypoxia pathways are dependent on ARNT, prior activation may deplete the cell of available ARNT for AHR heterodimerization (97MI3). 

Mellado, M., Rodriguez-Frade, J. M., Vila-Coro, A. J., Fernandez, S., MartindeAna, A., Jones, D. R., Toran, J. L., and Mardnez-Aet, C. (2001). Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. EMBO J. 20 2497-2507. 

Heterodimeric receptors, 182t Hetero dimerization, 181 Heterologous desensitization, 34 High-throughput screening agonists, 156 antagonists, 156... 

Bulenger S, Marullo S, Bouvier M (2005) Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation. Trends Pharmacol Sci 26 131-137... 

In addition, the alkaloid colchicine (from Colchicum autumnale) blocks tubulin polymerization by binding to heterodimeric (3-tubulin between amino acids 239 and 254. Since it inhibits the MT-dependent migration of granulocytes into areas of inflammation and their MT-dependent release of proinflammatory agents, it is used to treat attacks of gout. Its antimitotic effect in the gastrointestinal system induces diarrhoea. Nocodazole competes for the binding site of colchicine and has similar effects on heterodimeric (3-tubulin. 

The epidermal growth factor receptor 2 (HER-2) is a protein found on the surface of cells. Heterodimerization of HER-2 activates the enzyme tyrosine kinase, triggering reactions that cause the cells to grow and multiply. HER-2 is found at abnormally high levels on the surface of many types of cancer cells, which may divide excessively. Antibodies targeting HER-2 (e.g., trastuzumab) are used as antineoplastic agents. 

GM2 gangliosidosis (also known as Tay-Sachs disease) is a rare disorder caused by mutations in the gene encoding the lysosomal, heterodimeric ss-hexosaminidase... 

Integrins constitute a large family of a (3 heterodimeric cell surface, transmembrane proteins that interact with a large number of extracellular matrix components through a metal ion-dependent interaction. The term integrin reflects their function in integrating cell adhesion and migration with the cystoskeleton. 

Nuclear Receptor Regulation of Hepatic Cytochrome P450 Enzymes. Figure 1 General mechanism for transcriptional activation of CYP genes by xenochemicals that activate their cognate xeno-receptor proteins. In the case of Ah receptor, the receptor s heterodimerization partner is Arnt, whereas in the case of the nuclear receptors CAR, PXR, and PPARa, the heterodimerization partner is RXR. The coactivator and basal transcription factor complexes shown are each comprised of a large number of protein components. 

The existence of further alternative transcripts of MOP was postulated by the observation that in knockout mice with disrupted exon 1, heroin but not morphine was still analgesically active. Based on earlier observations that the antagonist naloxazone blocked morphine-induced antinociception but not morphine-induced respiratory depression, a subdivision of the MOP in pi and p2 was proposed. However, no discrete mRNA for each of these MOP subtypes has been found. It is, however, possible that subtypes of MOPs result from heterodimerization with other opioid receptors or by interaction with other proteins. 

There has been an extensive search for additional opioid receptor genes with homology to p, 8, and k receptors which was, however, unsuccessfiil. It is likely, therefore, that the functional properties of the subdivision of p, 8, and k receptors as well as that of the e and X receptors results from alternate mRNA processing, posttranslational modification of the receptor, and/ or from the formation of homo- and heterodimeric receptor complexes. 

All class I PI3Ks are heterodimeric enzymes composed of a 110 kDa catalytic subunit (with the isoforms pi 10 a,(3,5 or y) that associates with a regulatory subunit. Although the class I PI3Ks are capable of phosphorylating Ptdlns, PtdIns(4)P and PtdIns(4,5)P2 in vitro, it appears that they only use PtdIns(4,5)P2 as a substrate in vivo. Receptor-induced formation of Ptdlns... 

Potassium Competitive Acid Blockers The pregnane X receptor (PXR) is a promiscuous nuclear receptor, that has evolved to protect the body from toxic chemicals. It is activated by a wide variety of xenobiotics including several diugs like rifampicin, hyperforin ( the active ingredient of St. John s wort), clotrimazole and others. PXR heterodimerizes with the... 

Proton Pump Inhibitors and Acid Pump Antagonists retinoid X receptor (RXR) and is also activated by various lipophilic compounds produced by the body such as bile acids and steroids. PXR heterodimerized with RXR stimulates the transcription of cytochrome P450 3A monooxygenases (CYP3A) and other genes involved in the detoxification and elimination of the... 

GM2-gangl iosidosis Lysosomal, heterodimeric ss-hexosaminidase A (Hex A) Pyrimethamine... 

The retinoid X receptor (RXR) is a nuclear receptor that binds and is activated by certain endogenous retinoids, such as 9-cis-retinoic acid. RXR is the obligatory heterodimerization partner for a large number of nonclassic steroid nuclear receptors, such as thyroid hoimone receptor, vitamin D3 receptor, peroxisome proliferator-activated receptor and pregnane X receptor. 

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