Studies on a serine peptidase inhibitor locus on human chromosome 20 Characterization of novel genes encoding proteins with WFDC and kunitz domains

Adam Clauss

Research output: ThesisDoctoral Thesis (compilation)

Abstract

An unlimited number of proteolytic reactions are carried out by enzymes in biological systems. These enzymes are a necessity of life, but they can also be dangerous if they are not controlled. Protease inhibitors regulate proteolytic enzymes by interacting and forming complexes with them, thereby preventing the substrate from gaining access to the active site of the enzyme. We have recently identified a locus on human chromosome 20 that encompasses several genes that encode proteins containing one or more of the WFDC and kunitz serine protease domains. Among these genes are the previously described PI3 and SLPI. These new genes were first detected by their sequence similarity to the genes that encode the predominant gel-forming proteins in semen, semenogelin I and semenogelin II. To evaluate the function of these novel proteins, we used RT-PCR to study their expression pattern in a panel of tissues and cell lines. Most genes are ubiquitously expressed, although higher levels of expression have been detected in the male reproductive organs, including the seminal vesicles, epididymis, testes, and prostate. Expression has also been observed in the LNCaP and PC3 prostate cancer cell lines, the former of which is androgen sensitive and the latter androgen independent. The semenogelin genes have previously been described to be rapidly evolving. We identified and compared the locus of four mammalian species, and the results demonstrate that the genes are under evolutionary pressure, which is consistent with those involved in reproduction and/or immune defence. Three recombinant proteins were constructed in a prokaryote system to study their anti-proteolytic capacity. We did not detect any inhibitory effect on a panel of enzymes, possibly due to misfolding of the recombinant proteins. To circumvent this problem, we plan to construct new recombinant proteins in a eukaryotic system to ensure correct folding and disulphide paring.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Clinical Chemistry, Malmö
Supervisors/Advisors
  • Lundwall, Åke, Supervisor
Award date2006 May 24
Publisher
ISBN (Print)91-85559-10-5
Publication statusPublished - 2006

Bibliographical note

Defence details

Date: 2006-05-24
Time: 09:15
Place: Jubileumsaulan, Medicinskt forskningscentrum, Ing. 59, Universitetssjukhuset MAS

External reviewer(s)

Name: Ny, Tor
Title: Professor
Affiliation: Umeå University

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<div class="article_info">Åke Lundwall and Adam Clauss. <span class="article_issue_date">2002</span>. <span class="article_title">Identification of a novel protease inhibitor gene that is highly expressed in the prostate.</span> <span class="journal_series_title">Biochemical and biophysical research communications</span>, <span class="journal_pages">pp 452-456</span>. <span class="journal_distributor">Elsevier Science</span></div>
<div class="article_info">Adam Clauss, Hans Lilja and Åke Lundwall. <span class="article_issue_date">2002</span>. <span class="article_title">A locus on human chromosome 20 contains several genes expressing protease inhibitor domains with homology to whey acidic protein</span> <span class="journal_series_title">The Biochemical journal</span>, <span class="journal_pages">pp 233-242</span>. <span class="journal_distributor">Portland Press</span></div>
<div class="article_info">Adam Clauss, Hans Lilja and Åke Lundwall. <span class="article_issue_date">2005</span>. <span class="article_title">The evolution of a genetic locus encoding small serine proteinase inhibitors</span> <span class="journal_series_title">Biochemical and biophysical research communications</span>, <span class="journal_pages">pp 383-389</span>. <span class="journal_distributor">Elsevier Inc.</span></div>
<div class="article_info">Adam Clauss, Hans Lilja and Åke Lundwall. <span class="article_issue_date"></span>. <span class="article_title">Identification of three novel genes encoding kunitz motifs at the protease inhibitor locus on human chromosome 20</span> (manuscript)</div>

Subject classification (UKÄ)

  • Medicinal Chemistry

Free keywords

  • Medicin (människa och djur)
  • Medicine (human and vertebrates)
  • kunitz
  • Protase inhibitor
  • WFDC

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