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At least 379 records · Page 21Linked to original sources
PubMed1998

The molecular and phenotypic profile of primary central nervous system lymphoma identifies distinct categories of the disease and is consistent with histogenetic derivation from germinal center-related B cells.

Primary central nervous system lymphoma (PCNSL) is a major cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected individuals. The precise histogenetic derivation and the molecular pathogenesis of PCNSL is poorly understood. In an attempt to clarify the histogenesis and pathogenesis of these lymphomas, 49 PCNSL (26 acquired immunodeficiency syndrome [AIDS]-related and 23 AIDS-unrelated) were analyzed for multiple biologic markers, which are known to bear histogenetic and pathogenetic significance for mature B-cell neoplasms. PCNSL associated frequently (50.0%) with mutations of BCL-6 5' noncoding regions, which are regarded as a marker of B-cell transition through the germinal center (GC). Expression of BCL-6 protein, which is restricted to GC B cells throughout physiologic B-cell maturation, was detected in 100% AIDS-unrelated PCNSL and in 56.2% AIDS-related cases. Notably, among AIDS-related PCNSL, expression of BCL-6 was mutually exclusive with expression of Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP)-1 and, with few exceptions, also of BCL-2. All but one PCNSL expressed hMSH2, which among mature B cells selectively stains GC B cells. These data suggest that PCNSL may be frequently related to GC B cells and may be segregated into two major biologic categories based on the expression pattern of BCL-6, LMP-1, and BCL-2. BCL-6(+)/LMP-1(-)/BCL-2(-) PCNSL occur both in the presence and in the absence of HIV infection and consistently display a large noncleaved cell morphology. Conversely, BCL-6(-)/LMP-1(+)/BCL-2(+) PCNSL are restricted to HIV-infected hosts and are represented by lymphomas with immunoblastic features. These data are relevant for the pathogenesis and histogenesis of PCNSL and may be helpful to segregate distinct biologic and prognostic categories of these lymphomas.

B-Lymphocyte Subsets↗
PubMedDate not supplied

Inactivation of both Rb and p53 pathways in mouse lung epithelial cell lines.

Aberrant expression of key cell cycle regulatory genes is essential for the immortalization and transformation of cells in vitro. We examined 20 mouse lung epithelial cell lines (2 nontumorigenic, 5 nonmetastatic, and 13 metastatic) for mutations or alterations in the expression of key components of the Rb pathway (pRb and p16INK4a) and the p53 pathway (p53 and p19ARF). Seven cell lines had a mutation in exons 5 to 8 of p53. p19ARF was inactivated in the remaining 13 cell lines, primarily by homozygous deletion. Rb expression was present and unaltered in all cell lines, with both phosphorylated and unphosphorylated protein forms detectable. p16INK4a transcripts were undetectable in all cell lines tested except LM1. Loss of p16INK4a expression was a result of homozygous deletion in 11 out of 20 lung cell lines and promoter-exon 1 hypermethylation in 6 out of the remaining 8 cell lines. Other related components that were examined in this study included p21WAF1 and cyclin D1. Compared to normal lung tissue, p21WAF1 expression levels were reduced or undetectable in all cell lines, which did not correlate with loss of p53 function, but did correlate with inactivation of either p53 or p19ARF. Although cyclin D1 expression was variable between cell lines, transcript levels were decreased by at least 50% in the nontumorigenic lines C10 and E10 compared to the tumorigenic cell lines. These results demonstrate mutually exclusive relationships between p53 and p19ARF and between Rb and p16INK4a, but perhaps not between cyclin D1 and p16INK4a, and further describe the nature of involvement of both pathways in mouse lung tumorigenesis.

Animals↗
PubMed1995

Hepatocyte nuclear factor 1 alpha activates promoter 1 of the human insulin-like growth factor I gene via two distinct binding sites.

Expression of the human insulin-like growth factor I (hIGF-I) gene is regulated in a tissue- and developmental stage-specific manner. The hIGF-I gene has two promoters, P1 and P2. P1 is the more active promoter by far in adult liver, the main endocrine source of IGF-I. Recently, we described the involvement of the CAAT/enhancer binding protein family of liver-enriched transcription factors in the regulation of the expression of IGF-I in adult liver. In this study we report on the role of another family of liver-enriched transcription factors in the regulation of IGF-I expression. Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) is shown to transactivate IGF-I P1 in transient transfection experiments performed in Hep3B cells. Bandshift experiments reveal that two distinct regions in P1, located 119 and 282 nucleotides upstream of the transcription start site, can bind HNF-1 alpha with relatively high affinity. Both HNF-1-binding sites are evolutionary well conserved, emphasizing the importance of HNF-1 in the regulation of the IGF-I gene expression. Mutational analysis of the binding sites indicates that both sites are essential for maximal stimulation of P1 by HNF-1 alpha, although the largest contribution stems from the more downstream of the two HNF-1-binding sites. The latter site completely overlaps the previously described CAAT/enhancer binding protein binding site in P1. The colocalization of the binding sites, to which binding of the respective factors seems to be mutually exclusive, is suggestive of a regulatory hotspot to which members of different transcription factor families may bind depending on developmental stage and nutritional status.

Adult↗
PubMed1994

Transcriptional silencer of the human papillomavirus type 8 late promoter interacts alternatively with the viral trans activator E2 or with a cellular factor.

The noncoding region of the highly oncogenic, epidermodysplasia verruciformis-associated human papillomavirus type 8 contains a negative regulatory element (NRE). Quantitative RNase protection analysis confirmed that the NRE sequence acts as a silencer of transcription. A 38-bp sequence upstream of late promoter P7535 down-regulated expression from the homologous P7535 promoter, as well as the heterologous tk gene promoter, independently of its orientation relative to the test promoters. It also reduced gene expression when cloned downstream of the transcription units. Transient expression assays with keratinocytes and fibroblasts of epidermodysplasia verruciformis patients and controls demonstrated that the NRE activity is not cell specific. Gel retardation tests suggested that NRE specifically interacts with only one nuclear factor. Mutational analysis identified three NRE mutants which no longer formed a detectable DNA-protein complex but still repressed transcription, indicating that protein-DNA interaction is not relevant for the silencer function. The NRE contains a binding site of viral trans activator protein E2. It was shown that expression of E2 overrides the inhibitory effect of the NRE sequences. Binding of E2 and that of the cellular factor were mutually exclusive. The bifunctional nature of NRE acting as a silencer and a target site for viral trans activator E2 offers an interesting opportunity to regulate the switch from early to late transcription in the human papillomavirus life cycle.

Base Sequence↗
PubMed1999

Differential expression of AP-2alpha and AP-2beta in the developing chick retina: repression of R-FABP promoter activity by AP-2.

Retinal fatty acid binding protein (R-FABP) is the avian counterpart of murine brain FABP implicated in glial cell differentiation and neuronal cell migration. R-FABP is highly expressed in the undifferentiated retina and brain of chick embryos. We have previously shown by in vitro studies that the AP-2 transcription factor binds to a consensus AP-2 binding site in the R-FABP promoter region. Based on the expression pattern of AP-2 in the developing retina and on mutational analysis of the AP-2 binding site in DNA transfection experiments, we proposed that AP-2 could be involved in the down-regulation of R-FABP transcription. Here, we describe the cDNA isolation of two members of the AP-2 family expressed in the chick retina, AP-2alpha and AP-2beta. We show that R-FABP mRNA and the AP-2 factors are expressed in mutually exclusive patterns in the differentiating retina: whereas AP-2alpha and AP-2beta are selectively expressed either in amacrine, or in amacrine and horizontal cells, respectively, R-FABP mRNAis found in Muller glial cells and/or bipolar cells. Furthermore, a decrease in R-FABP-dependent expression is obtained upon cotransfection of primary retinal cultures with AP-2 expression vectors and a CAT reporter construct. The early and cell-specific expression of AP-2alpha and AP-2beta in the developing retina suggest a role for this transcription factor family in the early steps of amacrine and horizontal cell differentiation. Repression of the R-FABP gene in these cells may be an important component of their developmental program.

Amino Acid Sequence↗
PubMed2001

Absence of complementation in non-allelic mutants of Dictyostelium discoideum with defects in the transition from growth to development.

In Dictyostelium discoideum, growth and development are mutually exclusive and the transition between the two phases of the life cycle is regulated by the environment. This regulation is disturbed in HBW3, a chemically induced mutant with an unknown molecular defect. The mutant develops rapidly and expresses developmental markers during growth. Here we show that HBW3 fails to complement another mutant which has a similar phenotype: a targeted knock-out of the gdt1 gene. We further show that both mutations are recessive and that both are located on chromosome III, suggesting that the two mutations might be allelic. Molecular analysis, however, demonstrates that the gdt1 gene is not mutated in HBW3. Thus, although a wild-type copy of each gene is present in diploid cell lines, the defects due to the recessive mutations synergize to produce a detectable phenotype. The phenotypic similarities and differences between the two mutants are discussed.

Alleles↗
PubMed2005

Characterization of the intronic splicing silencers flanking FGFR2 exon IIIb.

The cell type-specific alternative splicing of FGFR2 pre-mRNA results in the mutually exclusive use of exons IIIb and IIIc, which leads to critically important differences in receptor function. The choice of exon IIIc in mesenchymal cells involves activation of this exon and repression of exon IIIb. This repression is mediated by the function of upstream and downstream intronic splicing silencers (UISS and DISS). Here we present a detailed characterization of the determinants of silencing function within UISS and DISS. We used a systematic mutational analysis, introducing deletions and substitutions to define discrete elements within these two silencers of exon IIIb. We show that UISS requires polypyrimidine tract-binding protein (PTB)-binding sites, which define the UISS1 sub-element, and an eight nucleotide sequence 5'-GCAGCACC-3' (UISS2) that is also required. Even though UISS2 does not bind PTB, the full UISS can be replaced with a synthetic silencer designed to provide optimal PTB binding. DISS is composed of a 5'-conserved sub-element (5'-CE) and two regions that contain multiple PTB sites and are functionally redundant (DISS1 and DISS2). DISS1 and DISS2 are separated by the activator sequence IAS2, and together these opposing elements form the intronic control element. Deletion of DISS in the FGFR2 exon IIIb context resulted in the near full inclusion of exon IIIb, and insertion of this silencer downstream of a heterologous exon with a weak 5' splice site was capable of repressing exon inclusion. Extensive deletion analysis demonstrated that the majority of silencing activity could be mapped to the conserved octamer CUCGGUGC within the 5'CE. Replacement of 5'CE and DISS1 with PTB-binding elements failed to restore repression of exon IIIb. We tested the importance of the relative position of the silencers and of the subelements within each silencer. Whereas UISS1, UISS2, DISS1, and DISS2 appear somewhat malleable, the 5'CE is rigid in terms of relative position and redundancy. Our data defined elements of function within the ISSs flanking exon IIIb and suggested that silencing of this exon is mediated by multiple trans-acting factors.

Alternative Splicing↗
PubMed2003

Regulation of differential COUP-TF-coregulator interactions in adrenal cortical steroidogenesis.

Hyperfunctioning adrenocortical adenomas produce excessive amounts of various corticosteroids due to dysregulated expression of steroidogenic enzymes. Since no genetic mutations in steroidogenic enzyme genes have been identified as yet, the dysregulated expression at the transcription level may be crucial. Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) and steroidogenic factor-1 (SF-1) play key roles in the transcriptional regulation of steroidogenic P450 genes. Transfection studies showed that SF-1 activated and COUP-TFs repressed the transcription of bovine CYP17 gene promoter from the CRS2 element in a mutually exclusive manner in Y-1 cells. The results indicate that COUP-TFs negatively regulate the transcriptional activity of SF-1, a steroidogenic cell-specific activator of various steroidogenic P450 genes. Expression of both COUP-TFI and COUP-TFII was significantly decreased in the cortisol-producing adenomas, in which CYP17 was drastically overexpressed, indicating that decreased expression of COUP-TFs play a key role in overexpression of CYP17 in this type of tumors. We then screened for COUP-TFI-interacting proteins from a cortisol-producing adenoma cDNA library using a yeast two-hybrid system and identified a novel RING finger-containing protein which can function as a coregulator for COUP-TFI. Notably, COUP-TFI activated rather than repressed several target genes including the human CYP11B2 gene promoter, the results of which were opposite to those of the CYP17 promoter. The bifunctional activities of COUP-TFI may be derived from the promoter context and our newly identified COUP-TFI coregulator.

Adrenal Cortex↗
PubMed1990

Promoter switching in Epstein-Barr virus during the initial stages of infection of B lymphocytes.

Transcription of the genes encoding the six viral nuclear antigens present in Epstein-Barr virus latently infected lymphocytes can be initiated from one of two promoters (Cp and Wp) mapping near the left end of the viral genome. These promoters are used in a mutually exclusive manner in clonal cell lines established from either Burkitt lymphoma tumors or in vitro infection of peripheral B lymphocytes. In this paper the role of Cp and Wp during viral latency is investigated. Cp appears to be the promoter normally employed during established latent infection. Analysis of two cell lines that use Wp revealed a deletion spanning Cp in the endogenous viral genomes, suggesting that cell lines exhibiting Wp activity harbor mutated viral genomes with a nonfunctional Cp. However, in contrast to the preferred usage of Cp exhibited by established Epstein-Barr virus-infected cell lines, Wp was shown to be exclusively utilized during the initial stages of viral infection. In addition to Wp activity, Cp usage was apparent by 6 days post-infection. A model is proposed involving B-lymphocyte differentiation-driven promoter switching during the establishment of viral latency.

Adult↗
PubMed2001

5'- and 3'-terminal nucleotides in the FGFR2 ISAR splicing element core have overlapping roles in exon IIIb activation and exon IIIc repression.

The cell type-specific, mutually-exclusive alternative splicing of the fibroblast growth factor receptor 2 (FGFR2) pre-mRNA is tightly regulated. A sequence termed ISAR (intronic splicing activator and repressor) has been implicated as an important cis regulatory element in both activation of exon IIIb and repression of exon IIIc splicing in epithelial cells. In order to better understand how this single sequence could have dual roles, we transfected minigenes containing a series of 2-bp mutations in the 18 3'-most nucleotides of ISAR that we refer to as the ISAR core. Transfection of cells with dual-exon (IIIb and IIIc) minigenes revealed that mutation of terminal sequences of the core led to decreased exon IIIb inclusion and increased exon IIIc inclusion. Transfection of cells with single-exon IIIb minigenes and single-exon IIIc minigenes revealed that mutation of terminal sequences of the ISAR core led to decreased exon IIIb inclusion and increased exon IIIc inclusion, respectively. Nucleotides of the ISAR core responsible for exon IIIb activation appear to overlap very closely with those required for exon IIIc repression. We describe a model in which ISAR and a 5' intronic sequence known as IAS2 form a stem structure required for simultaneous exon IIIb activation and exon IIIc repression.

Alternative Splicing↗
PubMed1990

A nucleotide substitution in a Bg1 II site is responsible for the RFLP discrimination between DPw4 and DPa.

In a previous work we showed that the two functionally different specificities DPw4 and DPa could only be differentiated by RFLP analysis using two mutually exclusive fragments (respectively, Bg1 II 5.29 kb for DPw4 and 7.24 kb for DPa). The DP Workshop synthetic analysis localized these fragments in the DPA2 pseudogene region. Our results demonstrate, however, that they are located between the A1 and B1 genes; the Bg1 II restriction site responsible for the 5.29 kb fragment was localized between the first and second exon of the DPB1 gene and inside the 7.24 kb fragment. A single mutation point inside this restriction site is responsible for the absence of the 5.29 kb fragment, changing the specificity attributed by RFLP typing.

Bacterial Proteins↗
PubMed2003

Negative feedback regulation ensures the one receptor-one olfactory neuron rule in mouse.

In the mouse olfactory system, each olfactory sensory neuron (OSN) expresses only one odorant receptor (OR) gene in a monoallelic and mutually exclusive manner. Such expression forms the genetic basis for OR-instructed axonal projection of OSNs to the olfactory bulb of the brain during development. Here, we identify an upstream cis-acting DNA region that activates the OR gene cluster in mouse and allows the expression of only one OR gene within the cluster. Deletion of the coding region of the expressed OR gene or a naturally occurring frame-shift mutation allows a second OR gene to be expressed. We propose that stochastic activation of only one OR gene within the cluster and negative feedback regulation by that OR gene product are necessary to ensure the one receptor-one neuron rule.

Alleles↗
PubMed1995

Agouti antagonism of melanocortin binding and action in the B16F10 murine melanoma cell line.

Several dominant mutations at the murine agouti locus result in the expression of a number of phenotypic changes, including a predominantly yellow coat color, obesity, and hyperinsulinemia. The mutants exhibit ectopic overexpression of normal agouti protein, suggesting that agouti regulates coat coloration by direct antagonism of the alpha-melanocyte-stimulating hormone receptor. We have tested this hypothesis by examining agouti inhibition of both melanocortin-stimulated cyclic adenosine monophosphate production and the binding of a radioactive melanocortin analog in the murine B16F10 melanoma cell line. Inhibition of melanocortin-induced cyclic nucleotide accumulation did not require preincubation of the cells with agouti and was independent of the agonist used. Furthermore, inhibition of both agonist binding to and activation of melanocortin receptor could be described by a simple competitive model with similar inhibition constants of 1.9 and 0.9 nM, respectively. The mutually exclusive binding of agouti and melanocortin was verified by cross-linking experiments using a radiolabeled alpha-melanocyte-stimulating hormone analog. Competitive inhibition of alpha-melanocyte-stimulating hormone binding can account for the effects of agouti on coat coloration and suggests the possibility that the other phenotypic changes observed on agouti overexpression may be due to direct action of agouti at a novel melanocortin receptor(s).

1-Methyl-3-isobutylxanthine↗
PubMed1996

YY1 and NF1 both activate the human p53 promoter by alternatively binding to a composite element, and YY1 and E1A cooperate to amplify p53 promoter activity.

A novel transcription factor binding element in the human p53 gene promoter has been characterized. It lies about 100 bp upstream of the major reported start site for human p53 gene transcription. On the basis of DNase I footprinting studies, electromobility shift assay patterns, sequence specificity of binding, the binding pattern of purified transcription factors, effects of specific antibodies, and methylation interference analysis we have identified the site as a composite element which can bind both YY1 and NF1 in an independent and mutually exclusive manner. The site is conserved in the human, rat, and mouse p53 promoters. The occupancy of the site varies in a tissue-specific manner. It binds principally YY1 in nuclear extracts of rat testis and spleen and NF1 in extracts of liver and prostate. This may facilitate tissue-specific control of p53 gene expression. When HeLa cells were transiently transfected with human p53 promoter-chloramphenicol acetyltransferase reporter constructs, a mutation in this composite element which disabled YY1 and NF1 binding caused a mean 64% reduction in basal p53 promoter activity. From mutations which selectively impaired YY1 or NF1 binding and the overexpression of YY1 or NF1 in HeLa cells we concluded that both YY1 and NF1 function as activators when bound to this site. In transient cotransfections E1A could induce the activity of the p53 promoter to a high level; 12S E1A was threefold as efficient as 13S E1A in this activity, and YY1 bound to the composite element was shown to mediate 55% of this induction. Overexpressed YY1 was shown to be able to synergistically activate the p53 promoter with E1A when not specifically bound to DNA. Deletion of an N-terminal domain of E1A, known to be required for direct E1A-YY1 interaction and E1A effects mediated through transcriptional activator p300, blocked the E1A induction of p53 promoter activity.

Animals↗
PubMed2005

Structural and mechanistic insights into the interaction between Rho and mammalian Dia.

Formins are involved in a variety of cellular processes that require the remodelling of the cytoskeleton. They contain formin homology domains FH1 and FH2, which initiate actin assembly. The Diaphanous-related formins form a subgroup that is characterized by an amino-terminal Rho GTPase-binding domain (GBD) and an FH3 domain, which bind somehow to the carboxy-terminal Diaphanous autoregulatory domain (DAD) to keep the protein in an inactive conformation. Upon binding of activated Rho proteins, the DAD is released and the ability of the formin to nucleate and elongate unbranched actin filaments is induced. Here we present the crystal structure of RhoC in complex with the regulatory N terminus of mammalian Diaphanous 1 (mDia1) containing the GBD/FH3 region, an all-helical structure with armadillo repeats. Rho uses its 'switch' regions for interacting with two subdomains of GBD/FH3. We show that the FH3 domain of mDia1 forms a stable dimer and we also identify the DAD-binding site. Although binding of Rho and DAD on the N-terminal fragment of mDia1 are mutually exclusive, their binding sites are only partially overlapping. On the basis of our results, we propose a structural model for the regulation of mDia1 by Rho and DAD.

Amino Acid Motifs↗
PubMed1998

Defective release of corepressor by hinge mutants of the thyroid hormone receptor found in patients with resistance to thyroid hormone.

On positive thyroid hormone response elements (pTREs), thyroid hormone receptor (TR) binding to DNA in the absence of ligand (thyroid hormone, T3) decreases transcription (silencing). Silencing is due to a family of recently described nuclear corepressor proteins (NCoR and SMRT) which bind to the CoR box in the hinge region of TR. Ligand-dependent activation of TR is associated with displacement of corepressors and recruitment of coactivating proteins. Resistance to thyroid hormone (RTH) is due to mutations in the beta isoform of the thyroid hormone receptor (TR-beta). To date, three RTH mutations reportedly with near-normal T3 binding (A234T, R243Q, and R243W) have been described in or near the CoR box. To determine the mechanism of RTH caused by these mutants, the interaction of wild type (wt) and mutant TRs with the corepressor, NCoR, and the coactivator, SRC-1, was tested in gel-shift assays. As expected, NCoR bound wt TR in the absence of T3 and dissociated from TR with increasing T3 concentration. SRC-1 failed to bind wt TR in the absence of T3, but bound to TR with increasing avidity as T3 concentrations rose. At no T3 concentration did both NCoR and SRC-1 bind to wt TR, indicating that their binding to TR was mutually exclusive. Hinge mutants bound NCoR normally in the absence of T3; however, dissociation of NCoR and recruitment of SRC-1 was markedly impaired except at very high T3 concentrations. Importantly, hinge mutant TRs when complexed to DNA bound T3 poorly despite their near-normal T3 binding in solution. These binding studies correlated with functional assays showing defective transactivation of pTREs by hinge mutants except at high T3 concentrations. Thus, we describe a novel mechanism of RTH whereby TR hinge mutants selectively affect T3 binding when complexed to DNA, and prevent NCoR dissociation from TR. Our data also suggest that solution T3 binding by RTH mutants may not accurately reflect physiologically relevant T3 binding by TR when bound to DNA.

DNA↗
PubMed2006

A greedy promoter controls malarial var-iations.

Immune evasion by the malaria parasite Plasmodium falciparum is mediated by the mutually exclusive expression of a single member of the var family of genes, which encode variant surface antigens. In a recent paper in Nature, demonstrate that a construct carrying a transcriptionally active var promoter is sufficient to promote allelic exclusion of the parasite's endogenous var gene.

Animals↗
PubMed1997

Individual residues contribute to multiple differences in ligand recognition between vesicular monoamine transporters 1 and 2.

Molecular cloning has identified two vesicular monoamine transporters (VMATs), one expressed in non-neural cells of the periphery (VMAT1) and the other by multiple monoamine cell populations in the brain (VMAT2). Functional analysis has previously shown that VMAT2 has a higher affinity than VMAT1 for monoamine neurotransmitters as well as the inhibitor tetrabenazine. The analysis of chimeric transporters has also identified two major regions required for the high affinity interactions of VMAT2 with these ligands. We have now used site-directed mutagenesis to identify the individual residues responsible for these differences. Focusing on the region that spans transmembrane domains 9 through 12, we have replaced VMAT2 residues with the corresponding residues from VMAT1. Many residues in this region had no effect on the recognition of these ligands, but substitution of Tyr-434 with Phe and Asp-461 with Asn reduced the affinity for tetrabenazine, histamine, and serotonin. Although the ability to affect recognition of multiple ligands suggests a general structural role for these residues, the mutations did not affect dopamine recognition, indicating a more specific role, possibly in recognition of the ring nitrogen that occurs in tetrabenazine, histamine, and serotonin but not dopamine. The mutation K446Q reduced the affinity of VMAT2 for tetrabenazine and serotonin but not histamine, whereas F464Y reduced serotonin affinity and perhaps histamine recognition but not tetrabenazine sensitivity, providing more evidence for specificity. Interestingly, the Vmax of both VMATs for dopamine exceeded that for serotonin by 3-5-fold, indicating a difference in the speed of packaging of these two neurotransmitters. We also found that VMAT1 has a higher affinity for tryptamine than VMAT2. This mutually exclusive interaction with serotonin and tryptamine also suggests a physiological rationale for the existence of two VMATs. Surprisingly, the residue responsible for this difference, Tyr-434, also accounts for the higher affinity interaction of VMAT2 with tetrabenazine, histamine, and serotonin. Interestingly, replacement of Tyr-434 with alanine increases the affinity of VMAT2 for both serotonin and dopamine and reduces the rate of dopamine transport.

Amino Acid Sequence↗