CoChat
Sign Up
PreprintCited by 9Enzyme Structure and FunctionProtease and Inhibitor MechanismsPeptidase Inhibition and Analysis

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Structure of puromycin-sensitive aminopeptidase and polyglutamine binding

Open access
Madabushi, Sowmya, Chow, K. Martin, Song, Eun Suk, Goswami, Anwesha, Hersh, Louis B., Rodgers, David W.·2023·PLoS ONE
DOI 10.1101/2023.05.30.542994PMC PMC10343166

Preprint — published as 10.1371/journal.pone.0287086 · Paper page

Open this paper in CoChat — free accountOpen PDF

Abstract

Puromycin-sensitive aminopeptidase (E.C. 3.4.11.14, UniProt P55786), a zinc metallopeptidase belonging to the M1 family, degrades a number of bioactive peptides as well as peptides released from the proteasome, including polyglutamine. We report the crystal structure of PSA at 2.3 Ǻ. Overall, the enzyme adopts a V-shaped architecture with four domains characteristic of the M1 family aminopeptidases, but it is in a less compact conformation compared to most M1 enzymes of known structure. A microtubule binding sequence is present in a C-terminal HEAT repeat domain of the enzyme in a position where it might serve to mediate interaction with tubulin. In the catalytic metallopeptidase domain, an elongated active site groove lined with aromatic and hydrophobic residues and a large S1 subsite may play a role in broad substrate recognition. The structure with bound polyglutamine shows a possible interacting mode of this peptide, which is supported by mutation.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/2023.05.30.542994

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 116

  1. 1988, Neuropeptides and their peptidases: functional considerations, Neurochem Int, 12, 383, 10.1016/0197-0186(88)90178-7 · DOI
  2. 1996, Ectoenzymes as sites of peptide regulation, Trends in Pharmaceutical Sciences, 17, 288, 10.1016/0165-6147(96)10036-5 · DOI
  3. 10.1146/annurev.ne.09.030186.002215 · DOI
  4. 10.1016/0076-6879(95)48015-3 · DOI
  5. 10.2174/0929866043406643 · DOI
  6. 10.1016/0009-8981(92)90154-I · DOI
  7. 10.1111/j.1471-4159.1981.tb02392.x · DOI
  8. 10.1038/286160a0 · DOI
  9. 1995, Degradation of dynorphin-related peptides by the puromycin-sensitive aminopeptidase and aminopeptidase M, J Neurochem, 65, 389, 10.1046/j.1471-4159.1995.65010389.x · DOI
  10. Puromycin-sensitive aminopeptidase, 1995, Sequence analysis, expression, and functional characterization, Journal of Biologial Chemistry, 270, 26931
  11. 10.1093/aob/mcq265 · DOI
  12. 10.1016/j.ydbio.2010.06.016 · DOI
  13. 2017, Sustained centrosome-cortical contact ensures robust polarization of the one-cell C. elegans embryo, Dev Biol, 422, 135, 10.1016/j.ydbio.2016.12.025 · DOI
  14. 2021, Puromycin-sensitive aminopeptidase is required for C2C12 myoblast proliferation and differentiation, J Cell Physiol, 236, 5293, 10.1002/jcp.30237 · DOI
  15. Benton D , Jaeger EC , Kilner A , Kimble A , Lowry J , Schleicher EM , et al. Interactions between the WEE-1.3 kinase and the PAM-1 aminopeptidase in oocyte maturation and the early C. elegans embryo. G3 (Bethesda). 2021;11(4). · DOI
  16. 2014, Genetic associations and functional characterization of M1 aminopeptidases and immune-mediated diseases, Genes Immun, 15, 521, 10.1038/gene.2014.46 · DOI
  17. 10.1200/JCO.2009.27.6295 · DOI
  18. 2017, Puromycin based inhibitors of aminopeptidases for the potential treatment of hematologic malignancies, Eur J Med Chem, 139, 325, 10.1016/j.ejmech.2017.07.048 · DOI
  19. 10.1210/me.15.6.960 · DOI
  20. 10.1210/me.15.6.882 · DOI
  21. 10.1242/dev.02615 · DOI
  22. 2003, The Caenorhabditis elegans orthologue of mammalian puromycin-sensitive aminopeptidase has roles in embryogenesis and reproduction, Journal of Biologial Chemistry, 278, 42795, 10.1074/jbc.M306216200 · DOI
  23. 10.1007/s00427-001-0194-z · DOI
  24. 10.1523/JNEUROSCI.19-14-06068.1999 · DOI
  25. 10.1016/j.neuron.2006.07.019 · DOI · Paper page
  26. 10.1021/bi061830d · DOI
  27. 10.1111/j.1479-8301.2010.00307.x · DOI
  28. 10.1093/hmg/ddr065 · DOI
  29. 10.1186/1750-1326-5-48 · DOI
  30. 10.1038/sj.emboj.7601592 · DOI
  31. 10.1093/hmg/ddq385 · DOI
  32. 2011, Zn-superoxide dismutase 1 (SOD1) is a novel target of Puromycin-sensitive aminopeptidase (PSA/NPEPPS): PSA/NPEPPS is a possible modifier of amyotrophic lateral sclerosis, Mol Neurodegener, 6, 29, 10.1186/1750-1326-6-29 · DOI
  33. 2003, Mutation of active site residues of the puromycin-sensitive aminopeptidase: conversion of the enzyme into a catalytically inactive binding protein. Arch, Biochem, Biophys, 413, 236
  34. 2003, Analysis of conserved residues of the human puromycin-sensitive aminopeptidase, Peptides, 24, 1359, 10.1016/j.peptides.2003.07.012 · DOI
  35. 10.1016/S0076-6879(97)76059-2 · DOI
  36. 1997, Processing of X-ray diffraction data collected in oscillation mode. Macromolecular Crystallography, Pt A, 276, 307
  37. 10.1016/j.jmb.2005.03.070 · DOI
  38. 10.1107/S2059798319011471 · DOI · Paper page
  39. 10.1107/S0907444909052925 · DOI · Paper page
  40. 10.1107/S0907444904019158 · DOI · Paper page
  41. 10.1110/ps.42301 · DOI
  42. 10.1073/pnas.0606167103 · DOI
  43. 2006, Crystal structure of aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition, Journal of Biologial Chemistry, 281, 33664, 10.1074/jbc.M605203200 · DOI
  44. 10.1073/pnas.0807398106 · DOI
  45. 10.1038/84117 · DOI
  46. 10.1073/pnas.1101262108 · DOI
  47. 10.1038/nsmb.2021 · DOI
  48. 10.1021/bi201230p · DOI
  49. 10.1016/0022-2836(82)90319-9 · DOI
  50. 10.1021/bi00270a034 · DOI
  51. 10.1016/0022-2836(72)90569-4 · DOI
  52. 10.1038/238041a0 · DOI
  53. 10.1038/238037a0 · DOI · Paper page
  54. 1974, The conformation of thermolysin, Journal of Biologial Chemistry, 249, 8030, 10.1016/S0021-9258(19)42067-X · DOI
  55. 10.1093/nar/gkh071 · DOI
  56. 10.1006/jmbi.2001.4624 · DOI
  57. 10.1016/S0003-9861(03)00200-5 · DOI
  58. 10.1073/pnas.1912070116 · DOI
  59. 2020, Discovery of Selective Inhibitors of Endoplasmic Reticulum Aminopeptidase 1, Journal of Medicinal Chemistry, 63, 103, 10.1021/acs.jmedchem.9b00293 · DOI
  60. 2021, Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism, Nat Commun, 12, 5302, 10.1038/s41467-021-25564-w · DOI
  61. 10.1016/S0960-894X(02)00845-4 · DOI
  62. 1989, A common amino acid sequence in 190-kDa microtubule-associated protein and tau for the promotion of microtubule assembly, Journal of Biologial Chemistry, 264, 5885, 10.1016/S0021-9258(18)83632-8 · DOI
  63. 10.1016/0896-6273(89)90050-0 · DOI · Paper page
  64. 10.1083/jcb.200201048 · DOI · Paper page
  65. 10.1073/pnas.1504081112 · DOI · Paper page
  66. 10.1186/gb-2004-6-1-204 · DOI · Paper page
  67. 10.1038/nature02393 · DOI
  68. 10.1016/j.str.2007.01.012 · DOI
  69. 10.1126/science.1221698 · DOI
  70. 10.1016/j.str.2013.04.018 · DOI
  71. 10.1083/jcb.201407095 · DOI
  72. 10.1038/386463a0 · DOI
  73. 2013, Structural insights into central hypertension regulation by human aminopeptidase A, Journal of Biologial Chemistry, 288, 25638, 10.1074/jbc.M113.494955 · DOI
  74. 2012, The X-ray crystal structure of human aminopeptidase N reveals a novel dimer and the basis for peptide processing, Journal of Biologial Chemistry, 287, 36804, 10.1074/jbc.M112.398842 · DOI
  75. 10.1073/pnas.1210123109 · DOI
  76. 10.1371/journal.ppat.1002859 · DOI
  77. 10.1038/nsmb.3048 · DOI
  78. 10.1002/pro.2604 · DOI
  79. 10.4049/jimmunol.1501103 · DOI
  80. 2008, Crystal structure of the cold-active aminopeptidase from Colwellia psychrerythraea, a close structural homologue of the human bifunctional leukotriene A4 hydrolase, Journal of Biologial Chemistry, 283, 23315, 10.1074/jbc.M802158200 · DOI
  81. 2018, Discovery, Structural and Biochemical Studies of a rare Glu/Asp Specific M1 Class Aminopeptidase from Legionella pneumophila, Int J Biol Macromol, 120, 1111
  82. 2020, Structural basis for the unusual substrate specificity of unique two-domain M1 metallopeptidase, Int J Biol Macromol, 147, 304, 10.1016/j.ijbiomac.2019.12.239 · DOI
  83. 2019, Two-domain aminopeptidase of M1 family: Structural features for substrate binding and gating in absence of C-terminal domain, J Struct Biol, 208, 51, 10.1016/j.jsb.2019.07.010 · DOI
  84. 10.1021/acs.jmedchem.6b01890 · DOI
  85. 10.1093/NAR/GKAB1061 · DOI · Paper page
  86. 10.1093/nar/gky473 · DOI · Paper page
  87. 10.1021/bi011409j · DOI
  88. 10.1042/bj3340407 · DOI
  89. 10.1038/nrm1782 · DOI
  90. 10.1146/annurev.neuro.23.1.217 · DOI
  91. 10.1073/pnas.96.8.4604 · DOI
  92. 10.1016/S0092-8674(00)80513-9 · DOI
  93. 10.1016/S1097-2765(04)00151-0 · DOI
  94. 1979, Isolation and characterization of an enkephalin-degrading aminopeptidase from rat brain, Biochemica Biophysica Acta, 569, 89, 10.1016/0005-2744(79)90084-6 · DOI
  95. 1981, Purification and characterization of an enkephalin aminopeptidase from rat brain, Biochemistry, 20, 3884, 10.1021/bi00516a034 · DOI
  96. 10.1105/tpc.104.024992 · DOI
  97. 10.1002/dvdy.10174 · DOI
  98. 10.1016/S0092-8674(00)81634-7 · DOI
  99. 2003, PepN, the major Suc-LLVY-AMC-hydrolyzing enzyme in Escherichia coli, displays functional similarity with downstream processing enzymes in Archaea and eukarya, Implications in cytosolic protein degradation. Journal of Biologial Chemistry, 278, 5548
  100. 1988, Major rat brain membrane-associated and cytosolic enkephalin-degrading aminopeptidases: comparison studies, J Neurosci Res, 20, 231, 10.1002/jnr.490200212 · DOI
  101. 10.1111/j.1471-4159.1985.tb04056.x · DOI
  102. 10.1111/j.1471-4159.1988.tb01124.x · DOI
  103. 10.1016/0143-4179(94)90083-3 · DOI
  104. 10.1042/bj3240517 · DOI
  105. Csuhai E , Safavi A , Thompson MW , Hersh LB . Proteolytic inactivation of secreted neuropeptides. In: Hook V , editor. Proteolytic and Cellular Mechanisms in Prohormone and Neuropeptide Precursor Processing. Heidelberg: Springer-Verlag; 1998.
  106. 10.1021/bi002715k · DOI
  107. 10.1016/j.chembiol.2008.07.018 · DOI
  108. 2015, Structural basis for the inhibition of M1 family aminopeptidases by the natural product actinonin: Crystal structure in complex with E. coli aminopeptidase N, Protein Science, 24, 823, 10.1002/pro.2653 · DOI
  109. 10.1093/nar/gkl082 · DOI
  110. 2020, Puromycin, a selective inhibitor of PSA acts as a substrate for other M1 family aminopeptidases: Biochemical and structural basis, Int J Biol Macromol, 165, 1373
  111. 2013, Small-molecule ligand docking into comparative models with Rosetta, Nature protocols, 8, 1277, 10.1038/nprot.2013.074 · DOI
  112. 10.1371/journal.pone.0132508 · DOI
  113. 10.1371/journal.pone.0063906 · DOI
  114. 2006, Degradation of amyotrophic lateral sclerosis-linked mutant Cu, Zn-superoxide dismutase proteins by macroautophagy and the proteasome, Journal of Biologial Chemistry, 281, 30524, 10.1074/jbc.M603337200 · DOI
  115. 10.1042/BST20120071 · DOI · Paper page
  116. 1997, Cloning of the human puromycin-sensitive aminopeptidase and evidence for expression in neurons, J Neurochem, 68, 889, 10.1046/j.1471-4159.1997.68030889.x · DOI

Metadata

Authors
Madabushi, S., Chow, K. M., Song, E. S., Goswami, A., Hersh, L. B., & Rodgers, D. W.
Affiliations
University of Kentucky (US)
Corresponding author
Rodgers, David W.
ORCID
Venue
PLoS ONE
Publisher
openRxiv
Published
2023-06-01
Volume
18
Issue
7
Pages
e0287086-e0287086
ISSN
1932-6203 (ISSN-L)
DOI
10.1101/2023.05.30.542994
PMC
PMC10343166
OpenAlex
W4384156328
Cited by
9
References
1
Citations by year
2026: 2 · 2025: 4 · 2024: 3
FWCI
0.66
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Science Foundation (1355438)
  • U.S. Department of Energy (1355438)
  • National Institutes of Health (NS38041)
  • National Institute on Drug Abuse (DA02243)
  • National Institute of General Medical Sciences (GM130954, P20GM103486, R01GM130954)
  • National Institute of Neurological Disorders and Stroke (R01NS038041, NS 38041)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Peptidase Inhibition and Analysis
Keywords
puromycin-sensitive aminopeptidase, zinc metallopeptidase, crystal structure, microtubule binding, substrate recognition, S1 subsite, active site, peptide degradation
MeSH terms
Aminopeptidases, Binding Sites, Peptides, Substrate Specificity, Metalloproteases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review