The serpin-enzyme complex (SEC) receptor mediates the neutrophil chemotactic effect of alpha-1 antitrypsin-elastase complexes and amyloid-beta peptide.

Joslin, Gregg; Griffin, Gail L.; August, A; Adams, Steve; Fallon, Robert J.; Senior, Robert M.; Perlmutter, David H.

doi:10.1172/jci115934

Cited by 73 publications

(52 citation statements)

References 21 publications

(3 reference statements)

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“…Radiolabeling of NE-NE was iodinated using the IODO-BEAD method according to the manufacturer's instructions (Pierce), as described previously (21). Briefly, two beads were washed in 500 l of PBS for 5 min and dried on filter paper.…”

Section: Methodsmentioning

confidence: 99%

Clathrin Pit-mediated Endocytosis of Neutrophil Elastase and Cathepsin G by Cancer Cells

Gregory

Hale

Perlmutter

et al. 2012

Journal of Biological Chemistry

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Background: Neutrophil elastase (NE)-induced tumor cell proliferation requires endosomal entry of the proteinase. Results: NE and CG bind to the surface of cancer cells and enter into tumor endosomes in a clathrin-and dynamin-dependent, caveolin-and flotillin-independent fashion. Conclusion: Entry of NE and CG into tumor endosomes occurs via classic clathrin-pit mediated endocytosis, which requires the binding of the proteinase to a cell surface receptor. Significance: This novel means of cell entry may grant tumor cells access to numerous, as yet unidentified bioactive molecules located in the extracellular environment.

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Section: Methodsmentioning

confidence: 99%

Clathrin Pit-mediated Endocytosis of Neutrophil Elastase and Cathepsin G by Cancer Cells

Gregory

Hale

Perlmutter

et al. 2012

Journal of Biological Chemistry

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“…Helices G and H are found under and behind/?-sheet B (in the orientation of Fig. l), covering the putative recognition site for the SEC receptor [30]. Any reorganization of the molecule to expose the recognition site must involve the movement of these helices away from their hydrophobic packing against sheet B.…”

Section: Cleaved Alpi*mentioning

confidence: 99%

“…The recognition sequence, buried and completely inaccessible in crystal structures of serpins, is supposed to become accessible after a serpin conformational change upon complexation with the protease. This putative change must be related to the transition after cleavage, since cleaved ollP1 competes with the a1PIIelastase complex for binding ( [30] and refs. therein), which is not easily reconcilable with the known crystal structure of alPI.…”

Section: Receptor Binding and Plasma Clearancementioning

confidence: 99%

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Structural aspects of serpin inhibition

et al. 1994

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The essential roles of proteins of the serpin family in many physiological processes, along with new discoveries of their unique folding properties, have attracted intense interest in recent years. Many serpins display unusual mobile behavior attributed to rearrangements of a-helical or /J-sheet domains, whereby large scale transitions accompany a variety of functions, including inactivation. This unusual behavior was first recognized with the X-ray structure of modified al-proteinase inhibitor. Subsequent experiments, including new X-ray structures, have revealed a surprising variety of conformations which are functionally important but only partially understood. We review here experimental evidence for conformations relevant to the serpin inhibitory mechanism.

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“…Both of these reactions cause a loss of inhibitor activity and, in the case of ␣ 1 -AT, it results in a ␣ 1 -AT molecule composed of two associated chains, a long amino-terminal fragment and a 36-residue carboxyl-terminal fragment, C-36 (5). This cleaved form of ␣ 1 -AT has been shown to have biological activities, such as chemotatic activity (6) and regulation of native ␣ 1 -AT synthesis (7). These observations support the notion that ␣ 1 -AT may also act as a reservoir of these biological activities that are released upon cleavage of the native form.…”

mentioning

confidence: 99%

Suppression of Cholesterol 7α-Hydroxylase Transcription and Bile Acid Synthesis by an α1-Antitrypsin Peptide via Interaction with α1-Fetoprotein Transcription Factor

Gerbod-Giannone¹,

Castillo-Olivares

Janciauskiene

et al. 2002

Journal of Biological Chemistry

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␣ 1 -Antitrypsin (␣ 1 -AT) is a serum protease inhibitor that is synthesized mainly in the liver, and its rate of synthesis markedly increases in response to inflammation. This increase in ␣ 1 -AT synthesis results in an increase in peptides, like its carboxyl-terminal C-36 peptide (C-36), resulting from ␣ 1 -AT cleavage by proteases. Atherosclerosis is a form of chronic inflammation, and one of the risk factors is elevated plasma cholesterol levels. Because of the correlation between atherosclerosis, plasma cholesterol content, inflammation, and ␣ 1 -AT rate of synthesis, we investigated the effect of the C-36 serpin peptide on hepatic bile acid biosynthesis. We discovered that C-36 is a powerful and specific transcriptional down-regulator of bile acid synthesis in primary rat hepatocytes, through inhibition of the cholesterol 7␣-hydroxylase/CYP7A1 (7␣-hydroxylase) promoter. Mice injected with the C-36 peptide also showed a decrease in 7␣-hydroxylase mRNA. A mutated but very similar peptide did not have any effect on 7␣-hydroxylase mRNA or its promoter. The sterol 12␣-hydroxylase/ CYP8B1 (12␣-hydroxylase) promoter is also downregulated by the C-36 peptide in HepG2 cells but not by the mutated peptide. The DNA element involved in the C-36-mediated regulation of 7␣-and 12␣-hydroxylase promoters mapped to the ␣ 1 -fetoprotein transcription factor (FTF) site in both promoters. The C-36 peptide prevented binding of FTF to its target DNA recognition site by direct interaction with FTF. We hypothesize that the C-36 peptide specifically interacts with FTF and induces a conformational change that results in loss of its DNA binding ability, which results in suppression of 7␣-and 12␣-hydroxylase transcription. These results suggest that peptides derived from specific serum proteins may alter hepatic gene expression in a highly specific manner.Serine protease inhibitors (serpins) are the most common protease inhibitors in mammals and are part of the acute phase response. At sites of inflammation, proteolytic enzymes are released by neutrophils, platelets, mast cells, macrophages, or by any invading microorganisms. Because an uncontrolled proteolytic activity would result in serious unwanted destruction of surrounding tissues, the synthesis of serpins (i.e. ␣ 1 -antichymotrypsin, ␣ 1 -antitrypsin (␣ 1 -AT), 1 and plasminogen activator inhibitor I) is markedly increased (1) to restore homeostasis. Inhibitory serpins interact with their target proteases at a reactive site located within a loop structure of 30 -40 amino acid residues from the carboxyl-terminal end (2). Formation of a stable complex between ␣ 1 -AT and human leukocyte elastase results from the cleavage of the P 1 -PЈ 1 bond in the reactive site loop, generating a 4-kDa carboxyl-terminal fragment of 36 amino acids corresponding to residues 359 -394 (C-36), that remains non-covalently bound to the cleaved ␣ 1 -AT in complex with the protease (3). This reactive site loop is also susceptible to proteolysis by non-target proteases (4), which can give rise to the car...

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The serpin-enzyme complex (SEC) receptor mediates the neutrophil chemotactic effect of alpha-1 antitrypsin-elastase complexes and amyloid-beta peptide.

Cited by 73 publications

References 21 publications

Clathrin Pit-mediated Endocytosis of Neutrophil Elastase and Cathepsin G by Cancer Cells

Clathrin Pit-mediated Endocytosis of Neutrophil Elastase and Cathepsin G by Cancer Cells

Structural aspects of serpin inhibition

Suppression of Cholesterol 7α-Hydroxylase Transcription and Bile Acid Synthesis by an α1-Antitrypsin Peptide via Interaction with α1-Fetoprotein Transcription Factor

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