The α-factor mating pheromone of Saccharomyces cerevisiae: a model for studying the interaction of peptide hormones and G protein-coupled receptors

Naider, Fred; Becker, Jeffrey M.

doi:10.1016/j.peptides.2003.11.028

Cited by 85 publications

(102 citation statements)

References 148 publications

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“…For instance, strong polar amino acids that mediate helix interactions in transmembrane segments, and weak polar residues that participate in helix packing (Eilers et al, 2005), are mostly conserved between K. lactis and S. cerevisiae receptors. E, N and I. Aromatic residues located in TM5 (F204) and in TM6 (Y266) have been postulated as interaction points of the ScSte2p receptor with aromatic residues (W1 and W3) of the α-pheromone (Lin et al, 2003;Naider and Becker, 2004). Aromatic residues are also present in these positions in the KlSte2p receptor (Y in both positions) and may have a role in making contact with putative W residues of the K. lactis sexual pheromone (Coria et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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The KlSTE2 and KlSTE3 genes encode MATα‐ and MATa‐specific G‐protein‐coupled receptors, respectively, which are required for mating of Kluyveromyces lactis haploid cells

Torres-Quiroz

Kawasaki

Rodríguez-González

et al. 2006

Yeast

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Mating in yeast is initiated by binding of pheromone to G-protein-coupled receptors expressed in haploid cells. We analysed the role of KlSte2p and KlSte3p receptors in the Kluyveromyces lactis mating pathway. By sequence analysis, KlSte2p and KlSte3p are the homologues of the Saccharomyces cerevisiae α-pheromone and a-pheromone receptors, respectively. However, by expression experiments, we determined that KlSTE2 gene is expressed in the cells typified as MAT α and therefore is the receptor for the K. lactis a-pheromone and KlSTE3 gene is expressed in the MAT a cells and binds the α-pheromone. The KlSTE2 gene is silent in MAT a cells, while it is highly expressed in MATα cells, and conversely the KlSTE3 gene is expressed in MAT a cells and repressed in MATα cells. Disruption mutants of both genes were found to be sterile, and this defect is reversed by plasmidic copies of each gene. The cytoplasmic C-terminus of KlSte3p interacts strongly with the KlGpa1p (Gα) subunit, which is involved in the transduction of the pheromone stimulus to induce mating. Remarkably, this same domain does not interact with a constitutive active allele of the Gα subunit, indicating that the C-terminus is able to discriminate between the active (GTP-bound) and inactive (GDP-bound) forms of the Gα subunit.

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Section: Discussionmentioning

confidence: 99%

“…The N-terminus of these receptors is located extracellularly and, along with portions of extracellular loops, forms the binding pocket for pheromone (Naider and Becker, 2004). The long Cterminus extends into the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

The KlSTE2 and KlSTE3 genes encode MATα‐ and MATa‐specific G‐protein‐coupled receptors, respectively, which are required for mating of Kluyveromyces lactis haploid cells

Torres-Quiroz

Kawasaki

Rodríguez-González

et al. 2006

Yeast

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“…The interaction between Ste2p (␣-factor receptor encoded by the STE2 gene), a Saccharomyces cerevisiae pheromone receptor, and its ligand tridecapeptide ␣-factor (WHWLQLK-PGQPMY) is one of the most extensively studied models for the peptide ligand-GPCR relationship (13,14). Recently, we showed that the use of 3,4-dihydroxyphenylalanine (DOPA) incorporated into the ligand was very effective for specific cross-linking to Ste2p (15).…”

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confidence: 99%

Identification of Residue-to-residue Contact between a Peptide Ligand and Its G Protein-coupled Receptor Using Periodate-mediated Dihydroxyphenylalanine Cross-linking and Mass Spectrometry

Umanah

Huang

Ding

et al. 2010

Journal of Biological Chemistry

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G protein-coupled receptors (GPCRs)4 comprise the largest family of cell surface proteins present in the human genome responsible for communication between the internal and external environments in response to signal molecules, including hormones, pheromones, and neurotransmitters. GPCRs are characterized by the presence of seven membrane-spanning helical segments separated by alternating intracellular and extracellular loop regions (1-3). Despite their diverse ligands, all GPCRs perform similar functions, coupling the binding of ligands to the activation of specific heterotrimeric guanine nucleotide-binding proteins (G proteins), leading to the modulation of downstream effector proteins and molecules. Due to their involvement in a multitude of physiological functions, GPCRs are targeted by ϳ50% of the human drugs currently marketed (1,4,5). Detailed information about GPCR-ligand interactions is critical for our understanding of GPCR-ligand binding and function.Despite the differences in the binding mechanisms of various ligand groups in the GPCR family, there are some similarities that span this superfamily of proteins (1, 3, 6 -8). Ligand binding triggers conformational changes at the extracellular and transmembrane regions of the receptor, which are then propagated to the cytoplasmic surfaces, leading to G protein coupling and activation. Thus, ligand binding leads to the alteration of existing interhelical interactions, thereby promoting a set of new interactions that leads to a energetically favorable activated conformational state of the receptor (8, 9). Large ligands, such as proteins, bind to the extracellular loops of GPCRs, whereas small molecules like adrenergic agents bind within the transmembrane region of the receptor. Within the peptide-binding GPCRs, a combination of ligand binding to the extracellular loops followed by ligand penetra-

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“…Identifying compound 2a, as the active diastereomer is consistent with previous data for bulky D-and L-amino acid substitutions at position 9 of this peptide, where L-amino acids tended to decrease activity, whereas D-amino acids improved activity. [1] The activity of 2a in the halo assay was approximately 90% of the control peptide 1, which is remarkably high activity for such a drastic change in backbone structure. As shown by Naider and Becker, [1] amino acid substitutions throughout this peptide affect the affinity for the receptor and show that it is normally necessary to increase the rigidity of the backbone in a favorable conformation for receptor binding to increase the activity.…”

mentioning

confidence: 89%

“…[1] The activity of 2a in the halo assay was approximately 90% of the control peptide 1, which is remarkably high activity for such a drastic change in backbone structure. As shown by Naider and Becker, [1] amino acid substitutions throughout this peptide affect the affinity for the receptor and show that it is normally necessary to increase the rigidity of the backbone in a favorable conformation for receptor binding to increase the activity. It is surprising that a β-amino acid with the backbone flexibility provided by the extra methylene group still results in a peptide with satisfactory activity.…”

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confidence: 89%

Control of the Yeast Cell Cycle with a Photocleavable α‐Factor Analogue

et al. 2006

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The budding yeast Saccharomyces cerevisiae is widely used as a model organism for studying many biological processes and systems, particularly for understanding the cell cycle. The yeast peptide pheromone α-factor (WHWLQLKPGQPMY) activates the mating pathway in MATa cells, arresting the cell cycle in the G1 phase. This arrest is used as a tool for synchronizing yeast cultures and for investigating signaling events involved in the pathway and other processes related to morphogenesis and transcription. Herein we report the synthesis and activity of an α-factor analogue designed to control the on/off state of the mating signal. Incorporating a photocleavable residue at a flexible site in the peptide allowed UV degradation in situ to mimic the natural protease degradation of this signaling peptide. The control over the α-factor signal achieved serves as proof of concept for use of this analogue as a tool. It also and allows access to previously impractical experiments that will yield highly time-resolved information about the yeast cell cycle and mating pathway.

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The α-factor mating pheromone of Saccharomyces cerevisiae: a model for studying the interaction of peptide hormones and G protein-coupled receptors

Cited by 85 publications

References 148 publications

The KlSTE2 and KlSTE3 genes encode MATα‐ and MATa‐specific G‐protein‐coupled receptors, respectively, which are required for mating of Kluyveromyces lactis haploid cells

The KlSTE2 and KlSTE3 genes encode MATα‐ and MATa‐specific G‐protein‐coupled receptors, respectively, which are required for mating of Kluyveromyces lactis haploid cells

Identification of Residue-to-residue Contact between a Peptide Ligand and Its G Protein-coupled Receptor Using Periodate-mediated Dihydroxyphenylalanine Cross-linking and Mass Spectrometry

Control of the Yeast Cell Cycle with a Photocleavable α‐Factor Analogue

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