Genomic analysis of orthologous mouse and human olfactory receptor loci

Lane, Robert P.; Cutforth, Tyler; Young, Janet M.; Αθανασίου, Μαρία; Friedman, Cynthia; Rowen, Lee; Evans, Glen A.; Axel, Richard; Hood, Leroy; Trask, Barbara J.

doi:10.1073/pnas.131215398

Cited by 93 publications

(83 citation statements)

References 41 publications

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“…1 A). This gene structure is similar to that of OR genes expressed in the MOE (29)(30)(31)(32)(33). The 5Ј UTRs and regions immediately upstream of transcription start sites were examined for common regulatory features.…”

Section: V1r Homology In the Human Genomesupporting

confidence: 52%

Sequence analysis of mouse vomeronasal receptor gene clusters reveals common promoter motifs and a history of recent expansion

Lane

Cutforth

Axel

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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We have analyzed the organization and sequence of 73 V1R genes encoding putative pheromone receptors to identify regulatory features and characterize the evolutionary history of the V1R family. The 73 V1Rs arose from seven ancestral genes around the time of mouse-rat speciation through large local duplications, and this expansion may contribute to speciation events. Orthologous V1R genes appear to have been lost during primate evolution. Exceptional noncoding homology is observed across four V1R subfamilies at one cluster and thus may be important for locusspecific transcriptional regulation.

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Section: V1r Homology In the Human Genomesupporting

confidence: 52%

Sequence analysis of mouse vomeronasal receptor gene clusters reveals common promoter motifs and a history of recent expansion

Lane

Cutforth

Axel

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…After binding to a metal ion, however, the anionic charge is cancelled. For example, if we replace just that single anionic residue by Val, the HMM algorithm projects an entirely different structure for the specific sequence of hOR-o2d2 (21).…”

Section: Resultsmentioning

confidence: 99%

Is the olfactory receptor a metalloprotein?

Wang

Luthey‐Schulten

Suslick

2003

Proc. Natl. Acad. Sci. U.S.A.

131

116

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The sense of smell is arguably our most primal faculty and also the least understood. Even our own olfactorily impaired species is capable of detecting Ϸ10,000 distinct scents [ Odorants first bind to an OR, which then undergoes some structural change that triggers the G protein activation and the following cascade of events leading to nerve cell activity. The structural details of ORs, however, remain to be determined. In this paper, we will describe a hypothesis in which metal ions play an important role for odorant recognition. We analyze the predicted structure and consensus sequence of the ORs and propose a metal-binding site in the loop between fourth and fifth helix (4 -5 loop). We have prepared synthetically a pentapeptide that contains this putative binding site and find that it not only has high affinity for binding Cu(II) and Zn(II) ions, but that it also undergoes a dramatic transition to an ␣-helical structure upon metal ion binding. Based on these observations, we propose a ''shuttlecock'' mechanism for the possible structural change in ORs upon odorant binding. This mechanism involves membrane penetration of the 4 -5 loop after residue charge neutralization by metal ion binding.olfaction ͉ G protein-coupled receptors ͉ transmembrane protein I norganic chemists know as a rule of thumb that if a volatile compound is a good ligand for metal ion coordination complexes, it probably smells strongly; this observation has lead to recent advances in artificial olfaction (1). The only notable exceptions to this rule are CO and NO, which are produced endogenously as neural messengers (2) and, therefore, elicit no olfactory response. In general, the human olfactory system is extremely sensitive to amines and thiols (good ligands for metal ions) but not to alcohols (which are only weak ligands; ref.3), as shown in Fig. 1. For example, one can smell methylthiol at less than 1 ppb, methylamine at 18 ppb, but methanol only above 100 ppm, and methane is undetected even at 10 6 ppm.Odorants needs to bind to an olfactory receptor (OR) to trigger the cascade of events that finally enables us to smell: methylthiol is bound by some OR Ͼ1 million times stronger than the OR that responds to methanol, and methylamine is bound Ͼ100,000 times stronger than methanol. Differences in hydrogen bonding or van der Waals interactions are insufficient to account for this range, but differences in Lewis basicity to metal ions can. This range of affinities is critical to the pattern recognition processes proposed for neural computation (4).Thus, the most natural explanation to account for this odorant affinity difference is coordination to a metal ion bound in an OR. Cu(II) or Zn(II) are particularly likely candidates, because they have strong amine-and thiol-binding property and are frequently found in metalloproteins. More than two decades ago, Crabtree (7) prophetically speculated that Cu(I) might be found in ORs, because of the high olfactory sensitivity to amines and thiols.Consistent with the metalloprotein hypothesis, the ORs ...

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“…However, the concept of only a single OR transcription complex that stably associates with a single OR control region (Ref. 27; reviewed in Ref. 70) within a given OSN would provide a simple solution for the complex problem of gene-and allele-specific transcription.…”

Section: Discussionmentioning

confidence: 99%

Complex Transcription and Splicing of Odorant Receptor Genes

Volz

Ehlers

Younger

et al. 2003

Journal of Biological Chemistry

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Human major histocompatibility (human leucocyte antigen (HLA)) complex-linked odorant receptor (OR) genes are among the best characterized OR genes in the human genome. In addition to their functions as odorant receptors in olfactory epithelium, they have been suggested to play a role in the fertilization process. Here, we report the first in-depth analysis of their expression and regulation within testicular tissue. Sixteen HLA-linked OR and three non-HLA-linked OR were analyzed. One OR gene (hs6M1-16, in positive transcriptional orientation) exhibited six different transcriptional start sites combined with extensive alternative splicing within the 5 -untranslated region, the coding exon, and the 3 -untranslated region. Long distance splicing, exon sharing, and premature polyadenylation were features of another three OR loci (hs6M1-18, -21, and -27, all upstream of hs6M1-16, but in negative transcriptional orientation). Determination of the transcriptional start sites of these OR genes identified a region of 81 bp with potential bi-directional transcriptional activity. The results demonstrate that HLA-linked OR genes are subject to unusually complex transcriptional regulatory mechanisms.

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Genomic analysis of orthologous mouse and human olfactory receptor loci

Cited by 93 publications

References 41 publications

Sequence analysis of mouse vomeronasal receptor gene clusters reveals common promoter motifs and a history of recent expansion

Sequence analysis of mouse vomeronasal receptor gene clusters reveals common promoter motifs and a history of recent expansion

Is the olfactory receptor a metalloprotein?

Complex Transcription and Splicing of Odorant Receptor Genes

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