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83. Transposon-Facilitated DNA Sequencing

Author

Strathmann, Michael, Hamilton, Bruce A., Mayeda, Carol A., Simon, Melvin I., Meyerowitz, Elliot M., and Palazzolo, Michael J.

Published
1991

98. Molecular architecture of G [[alpha].sub.0] and the structural basis for RGS16-mediated deactivation

Author

Slep, Kevin C., Kercher, Michele A., Wieland, Thomas, Chen, Ching-Kang, Simon, Melvin I., and Sigler, Paul B.

Subjects
G proteins -- Properties, G proteins -- Control, Cellular signal transduction -- Research, Proteins -- Structure, Proteins -- Research, Science and technology
Abstract

Heterotrimeric G proteins relay extracellular cues from heptahelical transmembrane receptors to downstream effector molecules. Composed of an a subunit with intrinsic GTPase activity and a [beta][gamma] heterodimer, the trimeric complex dissociates upon receptor-mediated nucleotide exchange on the [alpha] subunit, enabling each component to engage downstream effector targets for either activation or inhibition as dictated in a particular pathway. To mitigate excessive effector engagement and concomitant signal transmission, the G[alpha] subunit's intrinsic activation timer (the rate of GTP hydrolysis) is regulated spatially and temporally by a class of GTPase accelerating proteins (GAPs) known as the regulator of G protein signaling (RGS) family. The array of G protein-coupled receptors, G[alpha] subunits, RGS proteins and downstream effectors in mammalian systems is vast. Understanding the molecular determinants of specificity is critical for a comprehensive mapping of the G protein system. Here, we present the 2.9 A crystal structure of the enigmatic, neuronal G protein G[[alpha].sub.o] in the GTP hydrolytic transition state, complexed with RGS16. Comparison with the 1.89 [Angstrom] structure of apo-RGS16, also presented here, reveals plasticity upon G[[alpha].sub.o] binding, the determinants for GAP activity, and the structurally unique features of G[[alpha].sub.o] that likely distinguish it physiologically from other members of the larger G[[alpha].sub.i] family, affording insight to receptor, GAP and effector specificity. G protein | GAP | RGS

Published
2008

99. G[[alpha].sub.i2]-mediated signaling events in the endothelium are involved in controlling leukocyte extravasation

Author

Pero, Ralph S., Borchers, Michael T., Spicher, Karsten, Ochkur, Sergei I., Sikora, Lyudmila, Rao, Savita P., Abdala-Valencia, Hiam, O'Neill, Katie R., Shen, Huahao, McGarry, Michael P., Lee, Nancy A., Cook-Mills, Joan M., Sriramarao, P., Simon, Melvin I., Birnbaumer, Lutz, and Lee, James J.

Subjects
Leukocytes -- Research, G proteins -- Structure, G proteins -- Research, Cellular signal transduction -- Research, Inflammation -- Research, Science and technology
Abstract

The trafficking of leukocytes from the blood to sites of inflammation is the cumulative result of receptor-ligand-mediated signaling events associated with the leukocytes themselves as well as with the underlying vascular endothelium. Our data show that G[[alpha].sub.i] signaling pathways in the vascular endothelium regulate a critical step required for leukocyte diapedesis. In vivo studies using knockout mice demonstrated that a signaling event in a non-lymphohematopoietic compartment of the lung prevented the recruitment of proinflammatory leukocytes. Intravital microscopy showed that blockade was at the capillary endothelial surface and ex vivo studies of leukocyte trafficking demonstrated that a G[[alpha].sub.i]-signaling event in endothelial cells was required for transmigration. Collectively, these data suggest that specific G[[alpha].sub.i2]-mediated signaling between endothelial cells and leukocytes is required for the extravasation of leukocytes and for tissue-specific accumulation. G proteins | inflammation | knockout mice | leukocyte trafficking | pulmonary models

Published
2007

100. Caenorhabditis elegans G[[alpha].sub.q] regulates egg-laying behavior via a PLC[beta]-independent and serotonin-dependent signaling pathway and likely functions both in the nervous system and in muscle

Author

Bastiani, Carol A., Gharib, Shahla, Simon, Melvin I., and Sternberg, Paul W.

Subjects
Caenorhabditis elegans -- Research, Biological sciences
Abstract

egl-30 encodes the single C. elegans ortholog of vertebrate G[[alpha].sub.q] family members We analyzed the expression pattern of EGL-30 and found that it is broadly expressed, with highest expression ill the nervous system and in pharyngeal muscle. We isolated dominant, gain-of-function alleles of egl-30 as intragenic revertants of an egl-30 reduction-of-function mutation. Using these gain-of-function mutants and existing reduction-of-function mutants, we examined the site and mode of action of EGL-30. On the basis of pharmacological analysis, it has been determined that egl-30 functions both in the nervous system and in the vulval muscles for egg-laying behavior. Genetic epistasis over mutations that eliminate detectable levels of serotonin reveals that egl-30 requires serotonin to regulate egg laying. Furthermore, pharmacological response assays strongly suggest that EGL-30 may directly couple to a serotonin receptor to mediate egg laying. We also examined genetic interactions with mutations in the gene that encodes the single C. elegans homolog of PLC[beta] and mutations in genes that encode signaling molecules downstream of PLC[beta]. We conclude that PLC[beta] functions in parallel with egl-30 with respect to egg laying or is not the major effector of EGL-30. hi contrast, PLC[beta]-mediated signaling is likely downstream of EGL-30 with respect to pharyngeal-pumping behavior. Our data indicate that there are multiple signaling pathways downstream of EGL-30 and that different pathways could predominate with respect to the regulation of different behaviors.

Published
2003

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