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Gene Review

HM13  -  histocompatibility (minor) 13

Homo sapiens

Synonyms: H13, IMP-1, IMP1, IMPAS, IMPAS-1, ...
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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


Biological context of HM13


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


Other interactions of HM13


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].


  1. Identification of signal peptide peptidase, a presenilin-type aspartic protease. Weihofen, A., Binns, K., Lemberg, M.K., Ashman, K., Martoglio, B. Science (2002) [Pubmed]
  2. Single protein production in living cells facilitated by an mRNA interferase. Suzuki, M., Zhang, J., Liu, M., Woychik, N.A., Inouye, M. Mol. Cell (2005) [Pubmed]
  3. Carbapenem-hydrolysing IMP-1 beta-lactamase in Klebsiella pneumoniae from Singapore. Koh, T.H., Babini, G.S., Woodford, N., Sng, L.H., Hall, L.M., Livermore, D.M. Lancet (1999) [Pubmed]
  4. Identification of the amino acid residues essential for proteolytic activity in an archaeal signal peptide peptidase. Matsumi, R., Atomi, H., Imanaka, T. J. Biol. Chem. (2006) [Pubmed]
  5. Novel in vivo model for the study of human immunodeficiency virus type 1 transcription inhibitors: evaluation of new 6-desfluoroquinolone derivatives. Stevens, M., Pollicita, M., Pannecouque, C., Verbeken, E., Tabarrini, O., Cecchetti, V., Aquaro, S., Perno, C.F., Fravolini, A., De Clercq, E., Schols, D., Balzarini, J. Antimicrob. Agents Chemother. (2007) [Pubmed]
  6. Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins. Friedmann, E., Lemberg, M.K., Weihofen, A., Dev, K.K., Dengler, U., Rovelli, G., Martoglio, B. J. Biol. Chem. (2004) [Pubmed]
  7. L-dopa effects on preprogramming and control activity in a skilled motor act in Parkinson's disease. Fattapposta, F., Pierelli, F., My, F., Mostarda, M., Del Monte, S., Parisi, L., Serrao, M., Morocutti, A., Amabile, G. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. (2002) [Pubmed]
  8. Psychophysical studies evaluating the feasibility of a speech processing strategy for a multiple-channel cochlear implant. Tong, Y.C., Blamey, P.J., Dowell, R.C., Clark, G.M. The Journal of the Acoustical Society of America. (1983) [Pubmed]
  9. 2000 SPP Salk Award Address. Financing pediatric psychology services: buddy, can you spare a dime? Rae, W.A. Journal of pediatric psychology. (2004) [Pubmed]
  10. Requirements for signal peptide peptidase-catalyzed intramembrane proteolysis. Lemberg, M.K., Martoglio, B. Mol. Cell (2002) [Pubmed]
  11. Isolation and characterization of a light chain variable region gene for human rheumatoid factors. Chen, P.P., Robbins, D.L., Jirik, F.R., Kipps, T.J., Carson, D.A. J. Exp. Med. (1987) [Pubmed]
  12. Stromal processing peptidase binds transit peptides and initiates their ATP-dependent turnover in chloroplasts. Richter, S., Lamppa, G.K. J. Cell Biol. (1999) [Pubmed]
  13. Intramembrane-cleaving aspartic proteases and disease: presenilins, signal peptide peptidase and their homologs. Martoglio, B., Golde, T.E. Hum. Mol. Genet. (2003) [Pubmed]
  14. Activity of ertapenem (MK-0826) versus Enterobacteriaceae with potent beta-lactamases. Livermore, D.M., Oakton, K.J., Carter, M.W., Warner, M. Antimicrob. Agents Chemother. (2001) [Pubmed]
  15. Efficient cleavage by signal peptide peptidase requires residues within the signal peptide between the core and E1 proteins of hepatitis C virus strain J1. Hope, R.G., McElwee, M.J., McLauchlan, J. J. Gen. Virol. (2006) [Pubmed]
  16. Prevalence of activating ras mutations in morphologically characterized thyroid nodules. Ezzat, S., Zheng, L., Kolenda, J., Safarian, A., Freeman, J.L., Asa, S.L. Thyroid (1996) [Pubmed]
  17. Intramembrane proteolytic cleavage by human signal peptide peptidase like 3 and malaria signal peptide peptidase. Nyborg, A.C., Ladd, T.B., Jansen, K., Kukar, T., Golde, T.E. FASEB J. (2006) [Pubmed]
  18. Novel class of polytopic proteins with domains associated with putative protease activity. Grigorenko, A.P., Moliaka, Y.K., Korovaitseva, G.I., Rogaev, E.I. Biochemistry Mosc. (2002) [Pubmed]
  19. Expression of the presenilin-like signal peptide peptidase (SPP) in mouse adult brain and during development. Urny, J., Hermans-Borgmeyer, I., Gercken, G., Schaller, H.C. Gene Expr. Patterns (2003) [Pubmed]
  20. Structural and idiotypic characterization of the L chains of human IgM autoantibodies with different specificities. Goñi, F.R., Chen, P.P., McGinnis, D., Arjonilla, M.L., Fernandez, J., Carson, D., Solomon, A., Mendez, E., Frangione, B. J. Immunol. (1989) [Pubmed]
  21. Signal peptide peptidase forms a homodimer that is labeled by an active site-directed gamma-secretase inhibitor. Nyborg, A.C., Kornilova, A.Y., Jansen, K., Ladd, T.B., Wolfe, M.S., Golde, T.E. J. Biol. Chem. (2004) [Pubmed]
  22. Differential localization and identification of a critical aspartate suggest non-redundant proteolytic functions of the presenilin homologues SPPL2b and SPPL3. Krawitz, P., Haffner, C., Fluhrer, R., Steiner, H., Schmid, B., Haass, C. J. Biol. Chem. (2005) [Pubmed]
  23. Signal peptide peptidase: biochemical properties and modulation by nonsteroidal antiinflammatory drugs. Sato, T., Nyborg, A.C., Iwata, N., Diehl, T.S., Saido, T.C., Golde, T.E., Wolfe, M.S. Biochemistry (2006) [Pubmed]
  24. Purification and properties of a novel chloroplast stromal peptidase. Processing of polyphenol oxidase and other imported precursors. Koussevitzky, S., Ne'eman, E., Sommer, A., Steffens, J.C., Harel, E. J. Biol. Chem. (1998) [Pubmed]
  25. A signal peptide peptidase (SPP) reporter activity assay based on the cleavage of type II membrane protein substrates provides further evidence for an inverted orientation of the SPP active site relative to presenilin. Nyborg, A.C., Jansen, K., Ladd, T.B., Fauq, A., Golde, T.E. J. Biol. Chem. (2004) [Pubmed]
  26. C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation. Wang, J., Beher, D., Nyborg, A.C., Shearman, M.S., Golde, T.E., Goate, A. J. Neurochem. (2006) [Pubmed]
  27. Switching the inside and the outside of aggregates of water-soluble block copolymers with double thermoresponsivity. Arotçaréna, M., Heise, B., Ishaya, S., Laschewsky, A. J. Am. Chem. Soc. (2002) [Pubmed]
  28. Impas 1 possesses endoproteolytic activity against multipass membrane protein substrate cleaving the presenilin 1 holoprotein. Moliaka, Y.K., Grigorenko, A., Madera, D., Rogaev, E.I. FEBS Lett. (2004) [Pubmed]
  29. Targeting presenilin-type aspartic protease signal peptide peptidase with gamma-secretase inhibitors. Weihofen, A., Lemberg, M.K., Friedmann, E., Rueeger, H., Schmitz, A., Paganetti, P., Rovelli, G., Martoglio, B. J. Biol. Chem. (2003) [Pubmed]
  30. Intramembrane proteolysis of signal peptides: an essential step in the generation of HLA-E epitopes. Lemberg, M.K., Bland, F.A., Weihofen, A., Braud, V.M., Martoglio, B. J. Immunol. (2001) [Pubmed]
  31. Mechanism of intramembrane proteolysis investigated with purified rhomboid proteases. Lemberg, M.K., Menendez, J., Misik, A., Garcia, M., Koth, C.M., Freeman, M. EMBO J. (2005) [Pubmed]
  32. Induction of obliterative airway disease in murine tracheal allografts by CD8+ CTLs recognizing a single minor histocompatibility antigen. Higuchi, T., Maruyama, T., Jaramillo, A., Mohanakumar, T. J. Immunol. (2005) [Pubmed]
  33. Antibodies to ribosomal P proteins of Trypanosoma cruzi in Chagas disease possess functional autoreactivity with heart tissue and differ from anti-P autoantibodies in lupus. Kaplan, D., Ferrari, I., Bergami, P.L., Mahler, E., Levitus, G., Chiale, P., Hoebeke, J., Van Regenmortel, M.H., Levin, M.J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
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