B Fig. 2. General structure of dimeric class C GPCRs. (A) Ribbon view of the crystal structure of the resting Roo (left, pdb Accession no. 1 EWT) and fully active Acc (right, pdb Accession no. 1 ISR) state of the m. Glu 1 VFT dimer, and apposition of two rhodopsin structures. The yellow subunit is in the front, whereas the blue subunit is in the back. Note the difference in the relative orientation of the two VFTs probably leading to a different mode of association of the two HDs within the dimer. (B) Scheme illustrating that agonist binding in one VFT can activate the HD of the same subunit (cis-activation) and. or the HD of the other subunit (trans-activation). In the wild-type heterodimeric GABAB receptor only transactivation occurs (agonist binding in the GABAB 1 VFT leads to the activation of the GABAB 2 HD), but both cis- and trans-activation occur in the homodimeric m. Glu receptors.
The Wnts make up a large family of secreted proteins with roles in pattern formation, cell fate decisions, axon guidance, and tumor formation. The most widely studied Wnt signaling pathway, the canonical pathway, has been reviewed in depth and involves the regulation of cellular ß-Catenin levels. 1, 2 Briefly, in the absence of Wnt, ß-Catenin is recruited to a multimolecular protein complex that includes Axin, APC, and the kinase GSK-3ß. ß-Catenin is phosphorylated by GSK 3ß, and subsequently ubiquitinated and targeted for proteasomal degradation. Wnt binding to its receptor Frizzled, and potential co-receptor LRP-5/6, suppresses GSK-3ß phosphorylation of ß-Catenin accumulates and binds to LEF/TCF transcription factors resulting in the activation of Wnt target genes. The adaptor protein Dishevelled lies downstream of the Frizzled receptor and is critical for Wnt-mediated effects on cellular ß-Catenin levels. The exact mechanism leading to the activation of Dishevelled remains unclear, although it may involve Ryk (related to tyrosine kinase), a catalytically inactive, atypical receptor tyrosine kinase
Tipos de proteínas G heterotriméricas Gt
Ciclo de activación de proteínas G heterotriméricas R R R R GDP GTP GDP Pi GDP GTP R
Proteínas G: interferencia en el ciclo activación/desactivación Reacción de mono-ADP-ribosilación de la subunidad por toxinas bacterianas ADP-ribosil transferasa Toxina colérica (vibrio cholerae) Cys Mono-ADP ribosila un residuo de Arg de s, , bloquea su actividad GTPasa y permanece constitutivamente activa nicotinamide Toxina Pertussis (Bortedella Pertussis) Mono-ADP ribosila un residuo de Cys de i, , y desacopla la proteína G del receptor
Fig. 2. A proposed model for desensitization to gonadotropic hormone in ovarian follicular cells (granulosa). Gonadotropins bind to a receptor of 7 -transmembrane domain on granulosa cells and activate the hormone sensitive adenylyl cyclase, PKA, and expression of steroid factors and enzymes. There are several possible points in this cascade of events that can lead to desensitization to the hormone: (1) internalization of the hormone–receptor complex, (2) phosphorylation of the receptor molecule either through arrestin–kinase pathway or independently, (3) down-regulation of AC expression, (4) up-regulation of RGS proteins, (5) elevation of c. AMP dependent phosphodiesterase, and (6) activation of MAPK, which down-regulate St. AR expression and steroidogenesis.
Fig. 1. β-arrestin “receptosome”: roles in internalization and signaling.
ADENILIL CICLASA
Left panel: the forskolin-binding site and active site of AC. The active site occurs at the interface of the C 1 a and C 2 a subunits of AC, which are represented in dark and light blue respectively. The structure is that of the complex of ACV-C 1 a and ACII-C 2 a. Forskolin, shown in stick representation and in red, binds in the cleft that contains the active site. The ATPanalogue (2, 3 -dideoxy 5 -ATP; DAD, in yellow) and two Mg 2+ ions (represented as orange spheres) are bound in the AC active site in this crystal structure.
Efectores de las proteínas G: Adenilil ciclasa Regulación de las isoformas de la AC
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