Disease relevance of HM13

• In humans, SPP activity is required to generate signal sequence-derived human lymphocyte antigen-E epitopes that are recognized by the immune system, and to process hepatitis C virus core protein [1].
• We designed a single-protein production (SPP) system in living E. coli cells that exploits the unique properties of MazF, a bacterial toxin that is an ssRNA- and ACA-specific endoribonuclease [2].
• Carbapenem-hydrolysing IMP-1 beta-lactamase in Klebsiella pneumoniae from Singapore [3].
• A detailed alignment of prokaryotic SPP sequences strongly suggested that the majority of archaeal enzymes, along with the bacterial enzyme from Bacillus subtilis, adopt the same catalytic mechanism for peptide hydrolysis [4].
• Two novel 6-desfluoroquinolone derivatives, HM-12 and HM-13, were evaluated for anti-human immunodeficiency virus (anti-HIV) activity in acutely, chronically, and latently HIV type 1 (HIV-1)-infected cell cultures and were found to behave as potent HIV-1 transcription inhibitors [5].

Psychiatry related information on HM13

• These are the two presenilins that activate signaling molecules and are implicated in Alzheimer's disease, signal peptide peptidase (SPP), required for immune surveillance, and four SPP-like candidate proteases (SPPLs), of unknown function [6].
• OBJECTIVES: The authors investigated whether preprogramming (Bereitschaftspotential, BP) and control activity (skilled performance positivity, SPP) in a bimanual, sequential skilled performance task (SPT) is sensitive to L-dopa administration in non-demented Parkinson's disease (PD) patients [7].
• The dynamic range of current, the pitch variation with repetition rate, and the difference limens for repetition rate were found to be similar to MPP and SPP [8].
• 2000 SPP Salk Award Address. Financing pediatric psychology services: buddy, can you spare a dime [9]?

High impact information on HM13

• The presenilin-type aspartic protease signal peptide peptidase (SPP) can cleave signal peptides within their transmembrane region [10].
• Previously, we isolated a Vk gene (Humkv325) from a human placenta that encodes RF light chains bearing the PSL2 and PSL3 CRI markers [11].
• We conclude that SPP contains a specific binding site for the transit peptide and additional proteolysis by SPP triggers its release [12].
• Because of its requirement for hepatitis C virus maturation and a possible immune modulatory role, SPP is also considered a potential therapeutic target [13].
• Sixteen residues, highly conserved among archaeal SPP homologue sequences, were selected and replaced by alanine residues [4].

Chemical compound and disease context of HM13

• The IMP-1 metallo-beta-lactamase conferred substantial ertapenem resistance (MIC, 128 microg/ml) in a porin-deficient Klebsiella pneumoniae strain, whereas a MIC of 6 microg/ml was recorded for its porin-expressing revertant [14].
• Maturation of hepatitis C virus (HCV) core protein requires cleavage by signal peptidase (SP) and signal peptide peptidase (SPP) at a signal peptide between core and the E1 glycoprotein [15].
• A G to A H13 codon substitution replacing an Asp for a Gly residue was detected in 1 papillary carcinoma [16].

Biological context of HM13

• These data provide strong evidence that the SPP and SPPL3 have conserved active sites and suggest that the active sites SPPL2b is distinct [17].
• Expression analysis of the hIMP1 gene (located on chromosome 20) was performed in human cell tissues and transfected cell cultures [18].
• The SPP-protein is encoded in mouse and man by 12 exons [19].
• Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins [6].
• We have determined the V region amino acid sequence and/or serologic markers (kIIIb, PSL2, and PSL3) of 24 IgM monoclonal autoantibodies with specificities of anti-gamma-globulin (RF), anti-I (cold agglutinin), anti-low density lipoprotein and anti-intermediate filaments [20].

Anatomical context of HM13

• Co-purification of two different epitope-tagged forms of SPP from a stably transfected cell line expressing both tagged versions demonstrated that the approximately 95-kDa band is a homodimer of SPP [21].
• The antiserum was used to demonstrate that SPP is oriented in the membrane of the endoplasmic reticulum with its carboxy-terminal tail extending into the cytosol [19].
• We demonstrate that SPPL2b is targeted through the secretory pathway to endosomes/lysosomes, whereas SPP and SPPL3 are restricted to the ER [22].
• Here we show that, upon isolation of membranes and solubilization with detergent, the biochemical characteristics of SPP are remarkably similar to gamma-secretase [23].
• The N-terminal part of this sequence is removed by a stromal processing peptidase (SPP), and the resulting intermediate is translocated across the thylakoid and processed to the mature protein [24].

Associations of HM13 with chemical compounds

• SPP has been reported as a glycoprotein of approximately 45 kDa [21].
• In a glycerol velocity gradient, SPP sedimented from approximately 100-200 kDa [21].
• This assay utilizes a substrate consisting of the NH2 terminus of the ATF6 transcription factor fused to a transmembrane domain susceptible to SPP cleavage in vitro [25].
• Apart from the two aspartate-containing active site motifs, the only other region that is conserved between PS and SPP is a PAL sequence at the C-terminus [26].
• Water-soluble block copolymers were prepared from the nonionic monomer N-isopropylacrylamide (NIPA) and the zwitterionic monomer 3-[N-(3-methacrylamidopropyl)-N,N-dimethyl]ammoniopropane sulfonate (SPP) by sequential free radical polymerization via the RAFT process [27].

Enzymatic interactions of HM13

• Impas 1 possesses endoproteolytic activity against multipass membrane protein substrate cleaving the presenilin 1 holoprotein [28].

Regulatory relationships of HM13

• These common features let us speculate that gamma-secretase inhibitors directed against presenilin may also inhibit signal peptide peptidase [29].

Other interactions of HM13

• Mutations in evolutionary invariant sites in hIMP1 or specific gamma-secretase inhibitors abolish the hIMP1-mediated endoproteolysis of PS1 [28].
• Intramembrane proteolytic cleavage by human signal peptide peptidase like 3 and malaria signal peptide peptidase [17].
• Signal peptide peptidase forms a homodimer that is labeled by an active site-directed gamma-secretase inhibitor [21].
• After cleavage from the pre-protein, we show that the liberated MHC class I signal peptide is further processed by signal peptide peptidase in the hydrophobic, membrane-spanning region [30].
• These enzymes include site-2 protease, gamma-secretase/presenilin, signal peptide peptidase and the rhomboids, and they have a wide range of cellular functions [31].

Analytical, diagnostic and therapeutic context of HM13

• Our initial characterization of SPP isolated from human brain and cell lines demonstrated that SPP is primarily present as an SDS-stable approximately 95-kDa protein on Western blots [21].
• Northern blot and in situ hybridization analysis revealed a widespread expression of SPP in many tissues [19].
• Thus, the goal of this study was to define the role of a single mHAg mismatch at the polymorphic H13 allele in the development of obliterative airway disease (OAD) after murine heterotopic tracheal transplantation [32].
• Competitive enzyme immunoassays demonstrated that cChHD anti-P antibodies bind to the acidic portions of peptide H13, as well as to peptide H26R, encompassing the second extracellular loop of the beta1 adrenoreceptor [33].
• A semi-quantitative estimation of the binding of cChHD anti-P antibodies to R13 and H13 using biosensor technology indicated that the average affinity constant was about 5 times higher for R13 than for H13 [33].

References