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035 a| (OCoLC)1456021844;

096 a| QU 143;

049 a| EREE;

100 1 a| Garrigues, Ryan J.,e| author.?| UNAUTHORIZED;

245 10 a| Molecular insights into the regulation of complement protease C1s by the multi-specific SERPIN C1 esterase inhibitor /c| by Ryan J. Garrigues.;

264 1 a| [Greenville, N.C.] :b| [East Carolina University],c| 2024.;

300 a| 1 online resources (101 pages) :b| color illustrations;

336 a| textb| txt2| rdacontent;

337 a| computerb| c2| rdamedia;

338 a| online resourceb| cr2| rdacarrier;

347 a| text fileb| application/pdfc| 4.73 MB2| rda;

490 1 a| ECU Brody School of Medicine dissertation;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

502 b| Ph.D.c| East Carolina Universityd| 2024.;

500 a| Presented to the Faculty of the Department of Microbiology and Immunology;

500 a| Advisor: Brandon Garcia;

500 a| Title from PDF t.p. (viewed January 9, 2026).;

520 3 a| Functioning as a sentinel of the innate immune response, the complement system is an evolutionarily ancient proteolytic cascade that is involved in the recognition, opsonization, and lysis of foreign pathogens and apoptotic cells. Initiation of this system is paramount to the potency of the immune response but must be carefully controlled by negative regulators to mitigate aberrant activation. One such regulator, known as C1 esterase inhibitor (C1-INH), is the only canonical complement regulator that directly inhibits the initiating proteases of the classical pathway of complement C1r and C1s. C1-INH is part of a superfamily of serine protease inhibitors (SERPIN), which covalently react with target proteases through a substrate-like reactive center loop (RCL). In addition to its regulatory role in complement, C1-INH is multi-specific targeting a dozen proteases of the coagulation, contact, and fibrinolytic systems. Dysregulation of C1-INH is most apparent in congenital loss-of-function mutations of its encoding gene SERPING1 which causes a chronic debilitating disease known as hereditary angioedema (HAE). However, the molecular basis for C1-INH recognition of any of its cognate proteases including C1s has yet to be elucidated. Towards this end we aimed to characterize the SERPIN domain of C1-INH using a bacterial expression system and determine the molecular basis for C1s interactions. Utilizing structure-guided site-directed mutagenesis coupled to a novel surface plasmon based C1s binding assay we show that C1-INH relies on an extensive binding surface outside of the RCL for full affinity. The implications of this structure to the fields of SERPIN biology are discussed.;

504 a| Includes bibliographical references.;

650 0 a| Serpins.=| ^A1096428;

650 2 a| protease C1?| UNAUTHORIZED;

650 2 a| Complement C1 Inhibitor Protein0| (DNLM)D050718=| ^A1381098;

650 2 a| Serpins0| (DNLM)D015843=| ^A1204483;

653 a| Complement System;

653 a| Proteases;

653 a| SERPIN;

653 a| Crystallography;

653 a| Surface Plasmon Resonance;

653 a| C1-INH;

700 1 a| Garcia, Brandon L.,e| degree supervisor.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Microbiology and Immunology.?| UNAUTHORIZED;

830 0 a| ECU Brody School of Medicine dissertation.?| UNAUTHORIZED;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/13669;

994 a| C0b| ERE;

596 a| 1 4;

998 a| 6477454;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 6477454-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 9/16/2024x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 6477454-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 9/16/2024x| ETDz| HERESOURCE;

Molecular insights into the regulation of complement protease C1s by the multi-specific SERPIN C1 esterase inhibitor / by Ryan J. Garrigues.

Author/creator	Garrigues, Ryan J. author.
Other author	Garcia, Brandon L., degree supervisor.
Other author	East Carolina University. Department of Microbiology and Immunology.
Format	Theses and dissertations
Publication	[Greenville, N.C.] : [East Carolina University], 2024.
Description	1 online resources (101 pages) : color illustrations
Supplemental Content	Access via ScholarShip
Subjects	Serpins. protease C1 Complement C1 Inhibitor Protein Serpins

Series	ECU Brody School of Medicine dissertation ECU Brody School of Medicine dissertation. UNAUTHORIZED
Summary	Functioning as a sentinel of the innate immune response, the complement system is an evolutionarily ancient proteolytic cascade that is involved in the recognition, opsonization, and lysis of foreign pathogens and apoptotic cells. Initiation of this system is paramount to the potency of the immune response but must be carefully controlled by negative regulators to mitigate aberrant activation. One such regulator, known as C1 esterase inhibitor (C1-INH), is the only canonical complement regulator that directly inhibits the initiating proteases of the classical pathway of complement C1r and C1s. C1-INH is part of a superfamily of serine protease inhibitors (SERPIN), which covalently react with target proteases through a substrate-like reactive center loop (RCL). In addition to its regulatory role in complement, C1-INH is multi-specific targeting a dozen proteases of the coagulation, contact, and fibrinolytic systems. Dysregulation of C1-INH is most apparent in congenital loss-of-function mutations of its encoding gene SERPING1 which causes a chronic debilitating disease known as hereditary angioedema (HAE). However, the molecular basis for C1-INH recognition of any of its cognate proteases including C1s has yet to be elucidated. Towards this end we aimed to characterize the SERPIN domain of C1-INH using a bacterial expression system and determine the molecular basis for C1s interactions. Utilizing structure-guided site-directed mutagenesis coupled to a novel surface plasmon based C1s binding assay we show that C1-INH relies on an extensive binding surface outside of the RCL for full affinity. The implications of this structure to the fields of SERPIN biology are discussed.
General note	Presented to the Faculty of the Department of Microbiology and Immunology
General note	Advisor: Brandon Garcia
General note	Title from PDF t.p. (viewed January 9, 2026).
Dissertation note	Ph.D. East Carolina University 2024.
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.

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Molecular insights into the regulation of complement protease C1s by the multi-specific SERPIN C1 esterase inhibitor / by Ryan J. Garrigues.

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