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Activation Profiles and Regulatory Cascades of the Human Kallikrein-Related Peptidases

Title: Activation Profiles and Regulatory Cascades of the Human Kallikrein-Related Peptidases.
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Name(s): Yoon, Hyesook, author
Blaber, Michael, professor directing dissertation
Tang, Hengli, outside committee member
Miller, Brian, committee member
Steinbock, Oliver, committee member
Department of Chemistry and Biochemistry, degree granting department
Florida State University, degree granting institution
Type of Resource: text
Genre: Text
Issuance: monographic
Date Issued: 2008
Publisher: Florida State University
Place of Publication: Tallahassee, Florida
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: This work describes the activation profiles and regulatory cascades of the human kallikrein-related peptidases. The human kallikrein (KLK)-related peptidases are the largest family of serine peptidases, comprising 15 members (KLK1–15) and with the majority (KLK4–15) being identified only within the last decade. Members of this family are associated with important diseased states (including cancer, inflammation, and neurodegeneration) and have been utilized or proposed as clinically important biomarkers or therapeutic targets of interest. All human KLKs are synthesized as prepro-forms that are proteolytically processed to secreted pro-forms via the removal of an amino-terminal secretion signal peptide. The secreted inactive pro-KLKs are then activated extracellularly to mature peptidases by specific proteolytic release of their amino-terminal propeptide. Although a key step in the regulation of KLK function, details regarding the activation of the human pro-KLKs are unknown, to a significant extent, but have been postulated to involve "activation cascades" with other KLKs and endopeptidases. To characterize more completely the KLK activation cascades, an individual KLK propeptides fused to the amino terminus of a soluble carrier protein have been expressed from Escherichia coli. The ability of 14 different mature KLKs to process the 15 different pro-KLK peptide sequences has been determined. Various autolytic and cross activation relationships identified using this system have subsequently been characterized using recombinant pro-KLK proteins. The results demonstrate the potential for extensive KLK activation cascades and, when combined with available data for the tissue-specific expression of the KLK family, permit the construction of specific regulatory cascades. One such tissue-specific cascade is proposed for the central nervous system. Much recent work has been devoted to elucidating the potential for activation cascades between members of the KLK family, with physiologically relevant KLK regulatory cascades now described in skin desquamation and semen liquefaction. Despite this expanding knowledge of KLK regulation, details regarding the potential for functional intersection of KLKs with other regulatory proteases are essentially unknown. To elucidate such interaction potential, the ability of proteases associated with thromostasis to hydrolyze the pro-peptide sequences of the KLK family have been characterized, using the previously described (chapter 2) pro-KLK fusion protein system. A subset of positive hydrolysis results were subsequently quantified with proteolytic assays using intact recombinant pro-KLK proteins. The results show that proteases of the thrombostasis family can efficiently activate specific pro-KLKs, uncovering for the first time the potential for important regulatory interactions between these two major protease families. Proteases of the thrombostasis system are activated under conditions of injury, inflammation, and tissue remodeling, such as occurs in various disease states, including cancer. Activation of KLKs by thrombostasis proteases is therefore relevant for KLK activity in such diseases states.
Identifier: FSU_migr_etd-0712 (IID)
Submitted Note: A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Degree Awarded: Degree Awarded: Fall Semester, 2008.
Date of Defense: Date of Defense: July 10, 2008.
Keywords: Thrombin, Plasmin, Thrombostasis, Inflammation, Kallikrein-Related Peptidase, Activation Cascade
Bibliography Note: Includes bibliographical references.
Advisory committee: Michael Blaber, Professor Directing Dissertation; Hengli Tang, Outside Committee Member; Brian Miller, Committee Member; Oliver Steinbock, Committee Member.
Subject(s): Biochemistry
Chemistry
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_migr_etd-0712
Host Institution: FSU

Choose the citation style.
Yoon, H. (2008). Activation Profiles and Regulatory Cascades of the Human Kallikrein-Related Peptidases. Retrieved from http://purl.flvc.org/fsu/fd/FSU_migr_etd-0712