User:Anat Levit/Sandbox 1
Prokineticin 1 (PK1) and its close homologue PK2 are two secreted proteins, which belong to the AVIT protein family. They are small related peptides of 80-90 amino acids in length, sharing 10 conserved cysteins, which create a five disulphide-bridged motif (colipase fold) and an identical amino-termini – AVIT. PK's are expressed in a wide array of peripheral tissues, including the steroidogenic glands (such as the ovary, testis and adrenal gland), but also in the gastrointestinal tract, nervous system, bladder, bone marrow and prostate.
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PKs exert their biological function through activation of two homologous G-protein coupled receptors (see Wikipedia: G protein-coupled receptors),
termed Prokineticin receptor 1 (PROKR1) and Prokineticin receptor 2 (PROKR2). These receptors share
, which is a high value among known GPCRs. The proteins diverse mainly in their extra and intra-cellular tails.
The prokineticin and their receptors are expressed in various tissues, including the cardiovascular, gastrointestinal, immune, reproductive, endocrine and nervous systems. The receptors have been shown to couple to Gq, Gi and Gs, thereafter mediating intracellular calcium mobilization, phosphorylation of p42/p44 MAPK, AKT and cAMP accumulation, respectively. Receptor activation has been shown to mediate proliferation, anti-apoptosis, differentiation and mobilization of target cells.
The prokineticin receptors have been found to be involved in various pathologies involving the cardiovascular, reproductive, endocrine and nervous systems. Notably, PROKR2 has been found to be with dilated cardiomyopathy, a hypogonadism caused by a deficiency of gonadotropin-releasing hormone (GnRH) (see Wikipedia: Kallmann syndrome). Except for V331M and R357W which are Leu and Asn in PROKR1, respectively, all other residues mutated in PROKR2 are identical in PROKR1. Interestingly, two of the mutated residues, W178 (4.50) and P290 (6.50), are two of the most conserved residues in family A GPCRs ().
Being highly homologues proteins, expressed in the same cell types and having similar nano-molar affinity to common ligands, it is of importance to understand the structural and functional differences between these receptors.
The receptors are made of seven transmembrane α-helices of approximately 30 residues in length, which are connected by intra and extracellular loops. The helices are placed in a lipidic environment, while the loop regions are surrounded by aqueous medium. Although progress has been achieved in recent years, GPCR crystallization is still an unresolved issue. An alternative approach for visualizing a protein's 3D structure is the homology modeling approach, where the target protein is built starting from the experimentally known 3D structure of a related protein.
The structural models presented here were generated using the I-TASSER server, based on the templates 1l9h, 3eml, 2rh1 for human PROKR1 and 1l9h, 3eml, 1f88, 2rh1 for PROKR2. These models will help us as we examine the possible differences between the receptors, specifically, differences in post-translational modifications such as receptor phosphorylation, and differences in ligand binding, i.e., binding site identification.