An overview of the serpin superfamily

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Abstract

Serpins are protease inhibitors that use a conformational change to inhibit target enzymes and are important in many proteolytic cascades, including the mammalian coagulation and inflammatory-response pathways.

Abstract

Serpins are a broadly distributed family of protease inhibitors that use a conformational change to inhibit target enzymes. They are central in controlling many important proteolytic cascades, including the mammalian coagulation pathways. Serpins are conformationally labile and many of the disease-linked mutations of serpins result in misfolding or in pathogenic, inactive polymers.

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Structure of a serpin-protease complex shows inhibition by deformation.

J. Huntington, R. Read, R Carrell (2000)

The serpins have evolved to be the predominant family of serine-protease inhibitors in man. Their unique mechanism of inhibition involves a profound change in conformation, although the nature and significance of this change has been controversial. Here we report the crystallographic structure of a typical serpin-protease complex and show the mechanism of inhibition. The conformational change is initiated by reaction of the active serine of the protease with the reactive centre of the serpin. This cleaves the reactive centre, which then moves 71 A to the opposite pole of the serpin, taking the tethered protease with it. The tight linkage of the two molecules and resulting overlap of their structures does not affect the hyperstable serpin, but causes a surprising 37% loss of structure in the protease. This is induced by the plucking of the serine from its active site, together with breakage of interactions formed during zymogen activation. The disruption of the catalytic site prevents the release of the protease from the complex, and the structural disorder allows its proteolytic destruction. It is this ability of the conformational mechanism to crush as well as inhibit proteases that provides the serpins with their selective advantage.

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Conformational disease.

Robin Carrell, David A. Lomas (1997)

Several diverse disorders, including the prevalent dementias and encephalopathies, are now believed to arise from the same general disease mechanism. In each, there is abnormal unfolding and then aggregation of an underlying protein. The gradual accumulation of these aggregates and the acceleration of their formation by stress explain the characteristic late or episodic onset of the clinical disease. The understanding of these processes at the molecular level is opening prospects of more rational approaches to investigation and therapy.

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Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells.

R Sager, A Anisowicz, A Thor … (1994)

A gene encoding a protein related to the serpin family of protease inhibitors was identified as a candidate tumor suppressor gene that may play a role in human breast cancer. The gene product, called maspin, is expressed in normal mammary epithelial cells but not in most mammary carcinoma cell lines. Transfection of MDA-MB-435 mammary carcinoma cells with the maspin gene did not alter the cells' growth properties in vitro, but reduced the cells' ability to induce tumors and metastasize in nude mice and to invade through a basement membrane matrix in vitro. Analysis of human breast cancer specimens revealed that loss of maspin expression occurred most frequently in advanced cancers. These results support the hypothesis that maspin functions as a tumor suppressor.

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Author and article information

Journal

Journal ID (nlm-ta): Genome Biol

Title: Genome Biology

Publisher: BioMed Central (London )

ISSN (Print): 1465-6906

ISSN (Electronic): 1465-6914

Publication date (Print): 2006

Publication date (Electronic): 30 May 2006

Volume: 7

Issue: 5

Page: 216

Affiliations

[1 ]Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne VIC 3800, Australia

[2 ]Victorian Bioinformatics Consortium, Monash University, Clayton Campus, Melbourne VIC 3800, Australia

[3 ]ARC Centre for Structural and Functional Microbial Genomics, Monash University, Clayton Campus, Melbourne VIC 3800, Australia

[4 ]Magee-Womens Research Institute, Children's Hospital of Pittsburgh, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

Article

Publisher ID: gb-2006-7-5-216

DOI: 10.1186/gb-2006-7-5-216

PMC ID: 1779521

PubMed ID: 16737556

SO-VID: a76ccd0c-9194-41ee-8a2e-60385cb654d4

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An overview of the serpin superfamily

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Genome Integrity

Most cited references 92

Structure of a serpin-protease complex shows inhibition by deformation.

Conformational disease.

Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells.

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Cited by 184

Most referenced authors 1,108