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)

Differences in assignments from those in the universal genetic code occur in codes of mitochondria. In this report, the published sequences of the mitochondrial genes for COI and ND1 in a platyhelminth (Fasciola hepatica) are examined and it is concluded that AAA may be a codon for asparagine instead of lysine, whereas AAG is the sole codon for lysine in this species.
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PMID:Evolution of the mitochondrial genetic code. IV. AAA as an asparagine codon in some animal mitochondria. 211 47

The 15,697-nucleotide sequence of Paracentrotus lividus mitochondrial DNA is reported. This genome codes for 2 rRNAs, 22 tRNAs, and 12 mRNAs which specify 13 subunits of the mitochondrial inner membrane respiratory complexes. The gene arrangement differs from that of other animal species. The two ribosomal genes 16 S and 12 S are separated by a stretch of about 3.3 kilobase pairs which contains the ND1 and ND2 genes and a cluster of 15 tRNA genes. The ND4L coding sequence is not contained in the ND4 mRNA but has its own mRNA which maps between the tRNA(Arg) and the Co II genes. The main noncoding region, located in the tRNA gene cluster, is only 132 nucleotides long, but contains sequences homologous to the mammalian displacement loop. Other short noncoding sequences are interspersed in the genome: they contain a conserved AT consensus which probably has a role in transcription or RNA processing. As regards the mitochondrial genetic code, the codons AGA and AGG specify serine and are recognized by a tRNA with a GCU anticodon, whereas AUA and AAA code for isoleucine and asparagine rather than for methionine and lysine. Except for ND4L which starts with AUC and ATPase 8 which starts with GUG, AUG is used as the initiation codon. In 11 out of 13 cases the genes terminate with the canonical stop codons UAA or UAG. These observations suggest that during invertebrate evolution each lineage developed its own mechanism of mitochondrial DNA replication and transcription and of RNA processing and translation.
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PMID:The complete nucleotide sequence, gene organization, and genetic code of the mitochondrial genome of Paracentrotus lividus. 254 76

The AAA ATPase p97/VCP is involved in many cellular events including ubiquitin-dependent processes and membrane fusion. In the latter, the p97 adaptor protein p47 is of central importance. In order to provide insight into the molecular basis of p97 adaptor binding, we have determined the crystal structure of p97 ND1 domains complexed with p47 C-terminal domain at 2.9 A resolution. The structure reveals that the p47 ubiquitin regulatory X domain (UBX) domain interacts with the p97 N domain via a loop (S3/S4) that is highly conserved in UBX domains, but is absent in ubiquitin, which inserts into a hydrophobic pocket between the two p97 N subdomains. Deletion of this loop and point mutations in the loop significantly reduce p97 binding. This hydrophobic binding site is distinct from the predicted adaptor-binding site for the p97/VCP homologue N-ethylmaleimide sensitive factor (NSF). Together, our data suggest that UBX domains may act as general p97/VCP/CDC48 binding modules and that adaptor binding for NSF and p97 might involve different binding sites. We also propose a classification for ubiquitin-like domains containing or lacking a longer S3/S4 loop.
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PMID:Structural basis of the interaction between the AAA ATPase p97/VCP and its adaptor protein p47. 1498 33

Improperly folded proteins in the endoplasmic reticulum (ER) are eliminated via ER-associated degradation, a process that dislocates misfolded proteins from the ER membrane into the cytosol, where they undergo proteasomal degradation. Dislocation requires a subclass of ubiquitin ligases that includes gp78 in addition to the AAA ATPase p97/VCP and its cofactor, the Ufd1-Npl4 dimer. We have previously reported that gp78 interacts directly with p97/VCP. Here, we identify a novel p97/VCP-interacting motif (VIM) within gp78 that mediates this interaction. We demonstrate that the VIM of gp78 recruits p97/VCP to the ER, but has no effect on Ufd1 localization. We also show that gp78 VIM interacts with the ND1 domain of p97/VCP that was shown previously to be the binding site for Ufd1. To evaluate the role of Ufd1 in gp78-p97/VCP-mediated degradation of CD3delta, a known substrate of gp78, RNA interference was used to silence the expression of Ufd1 and p97/VCP. Inhibition of p97/VCP, but not Ufd1, stabilized CD3delta in cells that overexpress gp78. However, both p97/VCP and Ufd1 appear to be required for CD3delta degradation in cells expressing physiological levels of gp78. These results raise the possibility that Ufd1 and gp78 may bind p97/VCP in a mutually exclusive manner and suggest that gp78 might act in a Ufd1-independent degradation pathway for misfolded ER proteins, which operates in parallel with the previously established p97/VCP-Ufd1-Npl4-mediated mechanism.
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PMID:The role of a novel p97/valosin-containing protein-interacting motif of gp78 in endoplasmic reticulum-associated degradation. 1698 18

The p97 AAA (ATPase associated with diverse cellular activities), also called VCP (valosin-containing protein), is an important therapeutic target for cancer and neurodegenerative diseases. p97 forms a hexamer composed of two AAA domains (D1 and D2) that form two stacked rings and an N-terminal domain that binds numerous cofactor proteins. The interplay between the three domains in p97 is complex, and a deeper biochemical understanding is needed in order to design selective p97 inhibitors as therapeutic agents. It is clear that the D2 ATPase domain hydrolyzes ATP in vitro, but whether D1 contributes to ATPase activity is controversial. Here, we use Walker A and B mutants to demonstrate that D1 is capable of hydrolyzing ATP and show for the first time that nucleotide binding in the D2 domain increases the catalytic efficiency (kcat/Km) of D1 ATP hydrolysis 280-fold, by increasing kcat 7-fold and decreasing Km about 40-fold. We further show that an ND1 construct lacking D2 but including the linker between D1 and D2 is catalytically active, resolving a conflict in the literature. Applying enzymatic observations to small-molecule inhibitors, we show that four p97 inhibitors (DBeQ, ML240, ML241, and NMS-873) have differential responses to Walker A and B mutations, to disease-causing IBMPFD mutations, and to the presence of the N domain binding cofactor protein p47. These differential effects provide the first evidence that p97 cofactors and disease mutations can alter p97 inhibitor potency and suggest the possibility of developing context-dependent inhibitors of p97.
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PMID:Specific inhibition of p97/VCP ATPase and kinetic analysis demonstrate interaction between D1 and D2 ATPase domains. 2487 61