Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50502 (Hip)
 7,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin I converting enzyme (ACE) was purified to homogeneity from porcine kidney in order to determine whether iodobradykinins bind to the enzyme and, if so, whether pGlu-Trp-Pro-Arg-Pro-Gin-Ile-Pro-Pro, SQ20881, a competitive ACE inhibitor, changes the conformation of the enzyme in such a way that it binds kinins with an affinity and specificity expected of a bradykinin (BK) receptor, i.e. where the BK potentiating action of SQ20881 involves an increase in the number of BK receptors due to a conformational change in ACE. 125I-Labeled derivatives of [Tyr1]-kallidin and [Tyr-8]-bradykinin bound to the EDTA-inhibited enzyme, and binding was inhibited by nonradioactive BK. [125I-Tyr5]-BK was not bound by the enzyme. Specificity of [125I-Tyr5]-kallidin (T1K) binding was tested with forty-eight BK analogs, and the concentrations of analogs that inhibited 50% of T1K binding were determined. BK at 1.6 +/- 0.3 X 10(-8) M inhibited 505 of T1K binding. In addition, the concentrations of analogs that decreased by 50% the rate of [3H]-Hip-Gly-Gly ([3H]-HGG) hydrolysis by ACE were assessed. BK at 1.2 +/- 0.2 X 10(-6) M decreased the rate of [3H]-HGG hydrolysis by 50%. A comparison between these concentrations of analogs for inhibition of T1K binding and [3H]-HGG hydrolysis yielded a high correlation coefficient (r = 0.85). The specificity of ACE binding was clearly different from that expected of a BK receptor. Compounds structurally unrelated to BK, such as 5Q20881, pGlu-Lys-Trp-Ala-Pro-OH (BPP5a) and angiotensin I, inhibited T1K binding and [3H]-HGG hydrolysis by ACE.
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PMID:Interactions of kinins with angiotensin I converting enzyme (kininase II). 614 Sep 24

The NH2-terminal sequence of 22 residues of rabbit lung angiotensin-converting enzyme has been determined as (NH2)Thr-Leu-Asp-Pro-Gly-Leu-Leu-Pro-Gly-Asp-Phe-Ala -Ala-Asp-Asn-Ala-Gly-Ala-Arg-Leu-Phe-Ala-. In the course of purification of the enzyme for structural analysis a protein of Mr = 82,000 with angiotensin-converting activity was separated from the major fraction containing the native enzyme (Mr = 140,000). This low-molecular-weight enzyme catalyzed the hydrolysis of the synthetic substrate Hip-His-Leu at a rate 23% of that with the native enzyme, and exhibited a similar Km value as well as behaviors towards various effectors of angiotensin-converting enzyme. Edman degradation of both the native and the 82K enzymes revealed that they contain identical amino acid sequences from the NH2-termini. This result and those of peptide mapping and carbohydrate and amino acid analyses indicate that the 82K enzyme is a fragment derived from the NH2-terminal portion of the native enzyme, and hence contains its catalytic site. Evidence has been obtained indicating that the active fragment was formed from the native enzyme during its elution from the antibody-affinity column with NH4OH: on treatment of the native enzyme (140K Mr) with 1 N NH4OH at room temperature, a cleavage occurred and two proteins with Mr = 82K and Mr = 62K were obtained. The 82K Mr fragment was found to be enzymatically active and to contain the same NH2-terminal sequence as the native enzyme. The other fragment (62K Mr) was devoid of the activity and was shown to derive from the COOH-terminal portion of the native enzyme by the peptide mapping and terminal analyses. Cleavage of a peptide bond with NH4OH is unusual and appears to be specific for the native angiotensin-converting enzyme from rabbit lung.
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PMID:Rabbit pulmonary angiotensin-converting enzyme: the NH2-terminal fragment with enzymatic activity and its formation from the native enzyme by NH4OH treatment. 631 8

Three distinct peptidyldipeptidases (exopeptidases releasing carboxyl terminal dipeptide residues) can be solubilized from nerve terminal membrane fractions from whole rat brain or striatum, and separated by ion exchange chromatography. Brain angiotensin-converting enzyme (PDP-1) cleaves Hip-His-Leu, but not 80 nM [3H-Tyr1, Leu5]-enkephalin, and is markedly inhibited by several specific inhibitors such as captopril, teprotide, and MK-422. Enkephalinase (PDP-2) cleaves 80 nM [3H-Tyr1, Leu5]-enkephalin, but not Hip-His-Leu; it is not inhibited by any of the standard competitive inhibitors of angiotensin-converting enzyme (all analogs of carboxyl-terminal peptide sequences Phe-Ala-Pro or Ala-Pro), but is strongly inhibited by captopril analogs such as thiorphan (Phe-Gly analog). A third peptidyldipeptidase (PDP-3) cleaves Hip-His-Leu, but not 80 nM [3H-Tyr1, Leu5]-enkephalin; it is inhibited by dipeptide analog inhibitors such as captopril and thiorphan, but not by longer peptides such as teprotide or tripeptide analog inhibitors such as MK-422. Both PDP-2 (enkephalinase) and PDP-3 are apparently present in nerve terminal membranes predominantly as inactive proenzyme precursors, which elute from DEAE-cellulose at high salt concentration, and are activated very slowly by a process involving one or more trypsin-like enzymes. Rechromatography of activated PDP-2 and PDP-3 achieves a nearly complete separation of the two enzymes, both markedly purified, since each is much less acidic than its proenzyme precursor. Purified enkephalinase does not appear to have any significant endopeptidase activity. It cleaves Hip-Phe-Arg 200 times more effectively than Hip-Phe-Arg-NH2, and appears to be quite selective for cleaving the terminal dipeptide residue, Phe-Arg, from bradykinin, with no release of the second dipeptide and no cleavage of the Gly4-Phe5 interior peptide bond.
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PMID:Purification and characterization of enkephalinase, angiotensin converting enzyme, and a third peptidyldipeptidase from rat brain. 631 70

Integration host factor (IHF) is a small, heterodimeric DNA-binding protein of Escherichia coli composed of two subunits, alpha and beta, encoded by the himA and hip genes, respectively. IHF binds to the minor groove at a consensus sequence and bends DNA. We mutagenized the hip gene and studied the activity of the mutant IHF proteins in vivo and in vitro. Substitutions at the C-terminal alpha-helix (alpha-helix 3) reduced IHF activity and relaxed the specificity to DNA without abolishing the ability of IHF to bend DNA. These results indicate that the C-terminal region of Hip participates in determining IHF specificity. Alanine substitutions in beta-strands 2 and 3 generally had no effect on IHF activity in vivo suggesting that individually, many of these residues make only small contributions to the binding of IHF to DNA. Replacing the single amino acid of Hip that differs from HU in a highly conserved region of the arm did not affect IHF activity. This finding led us to conclude that this region of Hip does not contribute to specific DNA recognition by IHF. The binding of IHF to DNA is probably not restricted to one domain, but requires the co-operative participation of a number of regions of the protein.
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PMID:Genetic and biochemical analysis of the integration host factor of Escherichia coli. 851 42

Kennedy's disease is a degenerative disorder of motor neurons caused by the expansion of a glutamine tract near the amino terminus of the androgen receptor (AR). Ligand binding to the receptor is associated with several post-translational modifications, but it is poorly understood whether these affect the toxicity of the mutant protein. Our studies now demonstrate that mutation of lysine residues in wild-type AR that are normally acetylated in a ligand-dependent manner mimics the effects of the expanded glutamine tract on receptor trafficking, misfolding, and aggregation. Mutation of lysines 630 or 632 and 633 to alanine markedly delays ligand-dependent nuclear translocation. The K632A/K633A mutant also undergoes ligand-dependent misfolding and aggregation similar to the expanded glutamine tract AR. This acetylation site mutant exhibits ligand-dependent 1C2 immunoreactivity, forms aggregates that co-localize with Hsp40, Hsp70, and the ubiquitin-protein isopeptide ligase (E3) ubiquitin ligase carboxyl terminus of Hsc70-interacting protein (CHIP), and inhibits proteasome function. Ligand-dependent nuclear translocation of the wild-type receptor and misfolding and aggregation of the K632A/K633A mutant are blocked by radicicol, an Hsp90 inhibitor. These data identify a novel role for the acetylation site as a regulator of androgen receptor subcellular distribution and folding and indicate that ligand-dependent aggregation is dependent upon intact Hsp90 function.
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PMID:Androgen receptor acetylation site mutations cause trafficking defects, misfolding, and aggregation similar to expanded glutamine tracts. 1467 Sep 46

Cellular levels of estrogen receptor-alpha (ERalpha) protein are regulated primarily by the ubiquitin-proteasome pathway. Dynamic interactions between ERalpha and the protein degradation machinery facilitate the down-regulation process by targeting receptor lysine residues for polyubiquitination. To date, the lysines that control receptor degradation have not been identified. Two receptor lysines, K302 and K303, located in the hinge-region of ERalpha, serve multiple regulatory functions, and we examined whether these might also regulate receptor polyubiquitination, turnover, and receptor-protein interactions. We used ERalpha-negative breast cancer C4-12 cells to generate cells stably expressing wild-type (wt)ERalpha or ERalpha with lysine-to-alanine substitutions at K302 and K303 (ERalpha-AA). In the unliganded state, ERalpha-AA displayed rapid polyubiquitination and enhanced basal turnover, as compared with wtERalpha, due to its elevated association with the ubiquitin ligase carboxy terminus of Hsc70-interacting protein (CHIP) and the proteasome-associated cochaperone Bag1. Treatment of C4-12 cells with either 17beta-estradiol (E2) or the pure antiestrogen ICI 182,780 (ICI) induced rapid degradation of wtERalpha via the ubiquitin-proteasome pathway; however, in the presence of these ligands, ERalpha-AA was less efficiently degraded. Furthermore, ERalpha-AA was resistant to ICI-induced polyubiquitination, suggesting that these lysines are polyubiquitinated in response to the antiestrogen and demonstrate a novel role for these two lysines in the mechanism of action of ICI-induced receptor down-regulation. The reduced stability of ERalpha-AA in the unliganded state and the increased stability of ERalpha-AA in the liganded state were concordant with reporter gene assays demonstrating that ERalpha-AA has lower basal activity but higher E2 inducibility than wtERalpha. These data provide the first evidence that K302/303 protect ERalpha from basal degradation and are necessary for efficient E2- and ICI-induced turnover in breast cancer cells.
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PMID:Estrogen receptor-alpha hinge-region lysines 302 and 303 regulate receptor degradation by the proteasome. 1838 50

We demonstrate here that both coat protein (CP) phosphorylation by protein kinase CK2 and a chaperone system formed by two heat shock proteins, CP-interacting protein (CPIP) and heat shock protein 70 (HSP70), are essential for potato virus A (PVA; genus Potyvirus) replication and that all these host proteins have the capacity to contribute to the level of PVA CP accumulation. An E3 ubiquitin ligase called carboxyl terminus Hsc70-interacting protein (CHIP), which may participate in the CPIP-HSP70-mediated CP degradation, is also needed for robust PVA gene expression. Residue Thr243 within the CK2 consensus sequence of PVA CP was found to be essential for viral replication and to regulate CP protein stability. Substitution of Thr243 either with a phosphorylation-mimicking Asp (CPADA) or with a phosphorylation-deficient Ala (CPAAA) residue in CP expressed from viral RNA limited PVA gene expression to the level of nonreplicating PVA. We found that both the CPAAA mutant and CK2 silencing inhibited, whereas CPADA mutant and overexpression of CK2 increased, PVA translation. From our previous studies, we know that phosphorylation reduces the RNA binding capacity of PVA CP and an excess of CP fully blocks viral RNA translation. Together, these findings suggest that binding by nonphosphorylated PVA CP represses viral RNA translation, involving further CP phosphorylation and CPIP-HSP70 chaperone activities as prerequisites for PVA replication. We propose that this mechanism contributes to shifting potyvirus RNA from translation to replication.
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PMID:Coat Protein Regulation by CK2, CPIP, HSP70, and CHIP Is Required for Potato Virus A Replication and Coat Protein Accumulation. 2785 53