Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetically based polycystic kidney diseases include autosomal dominant (ADPKD) and recessive (ARPKD) polycystic kidney diseases, nephronophthisis and medullary cystic disease. The PKD1 and PKD2 genes responsible for ADPKD and their respective encoded proteins polycystin-1 and polycystin-2 are under intense study and clues are developing as to their function and roles in the disease process. Structure-function analysis suggests that polycystins form multiprotein complexes with focal adhesion and cell-cell adherens junction proteins, which then initiate intracellular signaling events culminating in regulation of transcription of genes controlling proliferation and differentiation. Although less is known about the PKHD-encoded fibrocystin responsible for ARPKD or about the NPH1-encoded nephrocystin responsible for nephronophthisis, it is proposed that they function in the same cellular pathway involving protein-protein interactions, signal transduction and regulation of gene transcription. ADPKD epithelia are more adherent to collagen, less migratory, fail to recruit FAK to polycystin complexes and show aberrant, persistent expression of the fetal genes Erb-B2 and beta2 subunit of NaK-ATPase after birth. It is suggested that the function of the polycystin complex is to act as a key developmental regulator of renal tubule morphogenesis.
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PMID:The genes and proteins associated with poly-cystic kidney diseases. 1253 90

In addition to their role in motility, eukaryotic cilia serve as a distinct compartment for signal transduction and regulatory sequestration of biomolecules. Recent genetic and biochemical studies have revealed an extraordinary diversity of protein complexes involved in the biogenesis of cilia during each cell cycle. Mutations in components of these complexes are at the heart of human ciliopathies such as Nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS), Bardet-Biedl syndrome (BBS) and Joubert syndrome (JBTS). Despite intense studies, proteins in some of these complexes, such as the NPHP1-4-8 and the MKS, remain poorly understood. Using a combination of computational analyses we studied these complexes to identify novel domains in them which might throw new light on their functions and evolutionary origins. First, we identified both catalytically active and inactive versions of transglutaminase-like (TGL) peptidase domains in key ciliary/centrosomal proteins CC2D2A/MKS6, CC2D2B, CEP76 and CCDC135. These ciliary TGL domains appear to have originated from prokaryotic TGL domains that act as peptidases, either in a prokaryotic protein degradation system with the MoxR AAA+ ATPase, the precursor of eukaryotic dyneins and midasins, or in a peptide-ligase system with an ATP-grasp enzyme comparable to tubulin-modifying TTL proteins. We suggest that active ciliary TGL proteins are part of a cilia-specific peptidase system that might remove tubulin modifications or cleave cilia- localized proteins, while the inactive versions are likely to bind peptides and mediate key interactions during ciliogenesis. Second, we observe a vast radiation of C2 domains, which are key membrane-localization modules, in multiple ciliary proteins, including those from the NPHP1-4-8 and the MKS complexes, such as CC2D2A/MKS6, RPGRIP1, RPGRIP1L, NPHP1, NPHP4, C2CD3, AHI1/Jouberin and CEP76, most of which can be traced back to the last common eukaryotic ancestor. Identification of these TGL and C2 domains aid in the proper reconstruction of the Y-shaped linkers, which are key structures in the transitional zone of cilia, by allowing precise prediction of the multiple membrane-contacting and protein-protein interaction sites in these structures. These findings help decipher key events in the evolutionary separation of the ciliary and nuclear compartments in course of the emergence of the eukaryotic cell.
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PMID:Novel transglutaminase-like peptidase and C2 domains elucidate the structure, biogenesis and evolution of the ciliary compartment. 2298 10