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Structural investigation of the alpha-1-antichymotrypsin : Prostate-specific antigen complex by comparative model building

Villoutreix, Bruno O. ; Lilja, Hans LU orcid ; Pettersson, Kim ; Lövgren, Timo and Teleman, Olle (1996) In Protein Science 5(5). p.836-851
Abstract

Prostate-specific antigen (PSA), produced by prostate cells, provides an excellent serum marker for prostate cancer. It belongs to the human kallikrein family of enzymes, a second prostate-derived member of which is human glandular kallikrein-1 (hK2). Active PSA and hK2 are both 237-residue kallikrein-like proteases, based on sequence homology. An hK2 model structure based on the serine protease fold is presented and compared to PSA and six other serine proteases in order to analyze in depth the role of the surface-accessible loops surrounding the active site. The results show that PSA and hK2 share extensive structural similarity and that most amino acid replacements are centered on the loops surrounding the active site. Furthermore,... (More)

Prostate-specific antigen (PSA), produced by prostate cells, provides an excellent serum marker for prostate cancer. It belongs to the human kallikrein family of enzymes, a second prostate-derived member of which is human glandular kallikrein-1 (hK2). Active PSA and hK2 are both 237-residue kallikrein-like proteases, based on sequence homology. An hK2 model structure based on the serine protease fold is presented and compared to PSA and six other serine proteases in order to analyze in depth the role of the surface-accessible loops surrounding the active site. The results show that PSA and hK2 share extensive structural similarity and that most amino acid replacements are centered on the loops surrounding the active site. Furthermore, the electrostatic potential surfaces are very similar for PSA and hK2. PSA interacts with at least two serine protease inhibitors (serpins): alpha-1-antichymotrypsin (ACT) and protein C inhibitor (PCI). Three-dimensional model structures of the uncleaved ACT molecule were developed based upon the recent X-ray structure of uncleaved antithrombin. The serpin was docked both to PSA and hK2. Amino acid replacements and electrostatic complementarities indicate that the overall orientation of the proteins in these complexes is reasonable. In order to investigate PSA's heparin interaction sites, electrostatic computations were carried out on PSA, hK2, protein C, ACT, and PCI. Two heparin binding sites are suggested on the PSA surface and could explain the enhanced complex formation between PSA and PCI, while inhibiting the formation of the ACT-PSA complex. PSA, hK2, and their preliminary complexes with ACT should facilitate the understanding and prediction of structural and functional properties for these important proteins also with respect to prostate diseases.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Antichymotrypsin, Coagulation, Electrostatic potential, Human glandular kallikrein-1, Prostate cancer, Prostate-specific antigen, Protein C, Protein c inhibitor, Protein modeling, Serine protease, Serpin
in
Protein Science
volume
5
issue
5
pages
836 - 851
publisher
The Protein Society
external identifiers
  • pmid:8732755
  • scopus:0029983596
ISSN
0961-8368
DOI
10.1002/pro.5560050505
language
English
LU publication?
yes
id
22e8e20e-806f-4c49-8cd1-b61ad136f2d7
date added to LUP
2022-12-06 16:36:58
date last changed
2024-01-03 19:32:50
@article{22e8e20e-806f-4c49-8cd1-b61ad136f2d7,
  abstract     = {{<p>Prostate-specific antigen (PSA), produced by prostate cells, provides an excellent serum marker for prostate cancer. It belongs to the human kallikrein family of enzymes, a second prostate-derived member of which is human glandular kallikrein-1 (hK2). Active PSA and hK2 are both 237-residue kallikrein-like proteases, based on sequence homology. An hK2 model structure based on the serine protease fold is presented and compared to PSA and six other serine proteases in order to analyze in depth the role of the surface-accessible loops surrounding the active site. The results show that PSA and hK2 share extensive structural similarity and that most amino acid replacements are centered on the loops surrounding the active site. Furthermore, the electrostatic potential surfaces are very similar for PSA and hK2. PSA interacts with at least two serine protease inhibitors (serpins): alpha-1-antichymotrypsin (ACT) and protein C inhibitor (PCI). Three-dimensional model structures of the uncleaved ACT molecule were developed based upon the recent X-ray structure of uncleaved antithrombin. The serpin was docked both to PSA and hK2. Amino acid replacements and electrostatic complementarities indicate that the overall orientation of the proteins in these complexes is reasonable. In order to investigate PSA's heparin interaction sites, electrostatic computations were carried out on PSA, hK2, protein C, ACT, and PCI. Two heparin binding sites are suggested on the PSA surface and could explain the enhanced complex formation between PSA and PCI, while inhibiting the formation of the ACT-PSA complex. PSA, hK2, and their preliminary complexes with ACT should facilitate the understanding and prediction of structural and functional properties for these important proteins also with respect to prostate diseases.</p>}},
  author       = {{Villoutreix, Bruno O. and Lilja, Hans and Pettersson, Kim and Lövgren, Timo and Teleman, Olle}},
  issn         = {{0961-8368}},
  keywords     = {{Antichymotrypsin; Coagulation; Electrostatic potential; Human glandular kallikrein-1; Prostate cancer; Prostate-specific antigen; Protein C; Protein c inhibitor; Protein modeling; Serine protease; Serpin}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{836--851}},
  publisher    = {{The Protein Society}},
  series       = {{Protein Science}},
  title        = {{Structural investigation of the alpha-1-antichymotrypsin : Prostate-specific antigen complex by comparative model building}},
  url          = {{http://dx.doi.org/10.1002/pro.5560050505}},
  doi          = {{10.1002/pro.5560050505}},
  volume       = {{5}},
  year         = {{1996}},
}