Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The oligosaccharide sequences of glycoconjugates and the nature of the saccharide linkage were investigated in normal human testes by means of lectin histochemistry studies, at light and electron microscopy levels. Reaction to WGA was intense in the seminiferous epithelium and interstitium. MAA showed light reactivity in all cell types of the human seminiferous epithelium, the lamina propria and Leydig cells. UEA-I lectin labelled the lamina propria intensely and the seminiferous epithelium and Leydig cells slightly. A slight reaction to AAA was found in the seminiferous epithelium and in Leydig cells. ConA was labelled in Sertoli cells, germ cells and Leydig cells. The reaction to GNA lectin was similar although less intense. PNA labelling was slight in Sertoli cells, spermatogonia, and Leydig cells, and more intense in spermatocytes, spermatids and peritubular cells. Reaction to DSA was intense in the seminiferous epithelium and Leydig cells. HPA labelled all cell types in the seminiferous epithelium and Leydig cells slightly, and labelled peritubular cells intensely. SBA lectin showed a strong reaction in spermatids and a slight reaction in the lamina propria. The reactions to SNA, LTA, and DBA were negative in all testicular cell types. After beta-elimination pre-treatment, MAA, UEA-I, AAA, PNA, DSA, HPA and SBA reactions were all negative. Endo F/PNGase digestion suppressed reactivity to ConA y GNA. Staining for WGA decreased with Endo F/PNGase digestion and also after beta-elimination. Desialization increased reactivity to PNA, SBA and HPA lectins. These results indicate that the terminal sequences of oligosaccharide side-chains in spermatocytes and, principally, in spermatids are: fucose, mannose, Neu5Ac2,3Gal1,3GalNAc, Gal1,3GalNAc, Gal1,4GlcNAc, Neu5AcGalNAc and GalNAc (in O-glycosylated proteins); mannose (in N-glycosylated proteins) and GlcNAc (in both protein types). A sialic acid residue is added to galactose and GalNAc residues. Present findings also indicate that Sertoli cell glycoproteins are similar to those of spermatids, and that the terminal sugar residues in Leydig cells are GlcNAc, fucose, mannose, Neu5Ac2,3Gal1,3GalNAc, Gal1,3GalNAc, and Gal1,4GlcNAc. The lectin pattern of the lamina propria suggests the presence of GlcNAc, galactose, fucose and GalNAc.
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PMID:Lectin histochemistry of the human testis. 997 91

The AAA ATPase p97 is a ubiquitin-selective molecular machine involved in multiple cellular processes, including protein degradation through the ubiquitin-proteasome system and homotypic membrane fusion. Specific p97 functions are mediated by a variety of cofactors, among them peptide N-glycanase, an enzyme that removes glycans from misfolded glycoproteins. Here we report the three-dimensional structure of the aminoterminal PUB domain of human peptide N-glycanase. We demonstrate that the PUB domain is a novel p97 binding module interacting with the D1 and/or D2 ATPase domains of p97 and identify an evolutionary conserved surface patch required for p97 binding. Furthermore, we show that the PUB and UBX domains do not bind to p97 in a mutually exclusive manner. Our results suggest that PUB domain-containing proteins constitute a widespread family of diverse p97 cofactors.
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PMID:The PUB domain functions as a p97 binding module in human peptide N-glycanase. 1680 42

During endoplasmic reticulum-associated degradation, the multifunctional AAA ATPase p97 is part of a protein degradation complex. p97 associates via its N-terminal domain with various cofactors to recruit ubiquitinated substrates. It also interacts with alternative substrate-processing cofactors, such as Ufd2, Ufd3, and peptide:N-glycanase (PNGase) in higher eukaryotes. These cofactors determine different fates of the substrates and they all bind outside of the N-terminal domain of p97. Here, we describe a cofactor-binding motif of p97 contained within the last 10 amino acid residues of the C terminus, which is both necessary and sufficient to mediate interactions of p97 with PNGase and Ufd3. The crystal structure of the N-terminal domain of PNGase in complex with this motif provides detailed insight into the interaction between p97 and its substrate-processing cofactors. Phosphorylation of p97's highly conserved penultimate tyrosine residue, which is the main phosphorylation site during T cell receptor stimulation, completely blocks binding of either PNGase or Ufd3 to p97. This observation suggests that phosphorylation of this residue modulates endoplasmic reticulum-associated protein degradation activity by discharging substrate-processing cofactors.
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PMID:Studies on peptide:N-glycanase-p97 interaction suggest that p97 phosphorylation modulates endoplasmic reticulum-associated degradation. 1749 50

The AAA (ATPase associated with various cellular activities) p97 [also known as VCP (valosin-containing protein)] participates in numerous biological activities and is an essential component of the ubiquitin signalling pathway. A plethora of adaptors have been reported for p97, and increasing evidence is suggesting that it is through adaptor binding that p97 is diverted into different cellular pathways. Studying the interaction between p97 and its adaptors is therefore crucial to our understanding of the physiological roles of the protein. The interactions between p97 and the PUB [PNGase (peptide N-glycosidase)/ubiquitin-associated] domain of PNGase, the UBX (ubiquitin regulatory X) domain of p47, and the UBD (ubiquitin D) domain of Npl4 have been structurally characterized. UBX and UBD are structural homologues that share similar p97-binding modes; it is plausible that other proteins that contain a UBX/UBX-like domain also interact with p97 via similar mechanisms. In addition, several short p97-interacting motifs, such as VBM (VCP-binding motif), VIM (VCP-interacting motif) and SHP, have been identified recently and are also shared between p97 adaptors, hinting that proteins possessing the same p97-binding motif might also share common p97-binding mechanisms. In this review, we aim to summarize our current knowledge on adaptor binding to p97.
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PMID:Insights into adaptor binding to the AAA protein p97. 1820 87

The endoplasmic reticulum (ER) glycoprotein HMG-CoA reductase (HMGR) catalyzes the rate-limiting step in sterols biosynthesis. Mammalian HMGR is ubiquitinated and degraded by the proteasome when sterols accumulate in cells, representing the best example for metabolically controlled ER-associated degradation (ERAD). This regulated degradation involves the short-lived ER protein Insig-1. Here, we investigated the dislocation of these ERAD substrates to the cytosol en route to proteasomal degradation. We show that the tagged HMGR membrane region, HMG(350)-HA, the endogenous HMGR, and Insig-1-Myc, all polytopic membrane proteins, dislocate to the cytosol as intact full-length polypeptides. Dislocation of HMG(350)-HA and Insig-1-Myc requires metabolic energy and involves the AAA-ATPase p97/VCP. Sterols stimulate HMG(350)-HA and HMGR release to the cytosol concurrent with removal of their N-glycan by cytosolic peptide:N-glycanase. Sterols neither accelerate dislocation nor stimulate deglycosylation of ubiquitination-defective HMG(350)-HA((K89 + 248R)) mutant. Dislocation of HMG(350)-HA depends on Insig-1-Myc, whose dislocation and degradation are sterol independent. Coimmunoprecipitation experiments demonstrate sterol-stimulated association between HMG(350)-HA and Insig-1-Myc. Sterols do not enhance binding to Insig-1-Myc of HMG(350)-HA mutated in its sterol-sensing domain or of HMG(350)-HA((K89 + 248R)). Wild-type HMG(350)-HA and Insig-1-Myc coimmunoprecipitate from the soluble fraction only when both proteins were coexpressed in the same cell, indicating their encounter before or during dislocation, raising the possibility that they are dislocated as a tightly bound complex.
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PMID:Dislocation of HMG-CoA reductase and Insig-1, two polytopic endoplasmic reticulum proteins, en route to proteasomal degradation. 1945 99

Dendritic cells use a specialized pathway called cross-presentation to activate CD8+ T cells by presenting peptides from exogenous protein antigens on major histocompatibility complex class I molecules. Considerable evidence suggests that internalized antigens cross endocytic membranes to access cytosolic proteasomes for processing. The mechanism of protein dislocation represents a major unsolved problem. Here we describe the development of a sensitive reporter substrate, an N-glycosylated variant of Renilla luciferase fused to the Fc region of human IgG1. The luciferase variant is designed to be enzymatically inactive when glycosylated, but active after the asparagine to aspartic acid conversion that occurs upon deglycosylation by the cytosolic enzyme N-glycanase-1. The generation of cytosolic luminescence depends on internalization, deglycosylation, the cytosolic AAA-ATPase VCP/p97, and the cytosolic chaperone HSP90. By incorporating a T cell epitope into the fusion protein, we demonstrate that antigen dislocation into the cytosol is the rate limiting step in cross-presentation.
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PMID:A novel probe to assess cytosolic entry of exogenous proteins. 3008 32