Importance of the amino‐acid composition of the shutter region of plasminogen activator inhibitor‐1 for its transitions to latent and substrate forms

Hansen, Martin; Busse, Marta; Andreasen, Peter A.

doi:10.1046/j.0014-2956.2001.02582.x

Cited by 48 publications

(56 citation statements)

References 54 publications

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“…The likely limiting factor in the latent transition is not so much the opening of the A-sheet as the release of the intact loop by thermal dissociation at its distal hinge, s1C (25,45). This is consistent with previous observation that replacement of glutamine with histidine at 334 in plasminogen activator inhibitor-1 does not decrease latent transition (46).…”

Section: Discussionsupporting

confidence: 81%

Serpin Polymerization Is Prevented by a Hydrogen Bond Network That Is Centered on His-334 and Stabilized by Glycerol

Zhou

Stein

Huntington

et al. 2003

Journal of Biological Chemistry

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Polymerization of serpins commonly results from mutations in the shutter region underlying the bifurcation of strands 3 and 5 of the A-sheet, with entry beyond this point being barred by a H-bond network centered on His-334. Exposure of this histidine in antithrombin, which has a partially opened sheet, allows polymerization and peptide insertion to occur at pH 6 or less when His-334 will be predictably protonated with disruption of the H-bond network. Similarly, thermal stability of antithrombin is pH-dependent with a single unfolding transition at pH 6, but there is no such transition when His-334 is buried by a fully closed A-sheet in heparincomplexed antithrombin or in ␣ 1 -antitrypsin. Replacement of His-334 in ␣ 1 -antitrypsin by a serine or alanine at pH 7.4 results in the same polymerization and looppeptide acceptance observed with antithrombin at low pH. The critical role of His-334 and the re-formation of its H-bond network by the conserved P8 threonine, on the full insertion of strand 4, are relevant for the design of therapeutic blocking agents. This is highlighted here by the crystallographic demonstration that glycerol, which at high concentrations blocks polymerization, can replace the P8 threonine and re-form the disrupted H-bond network with His-334.

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Section: Discussionsupporting

confidence: 81%

Serpin Polymerization Is Prevented by a Hydrogen Bond Network That Is Centered on His-334 and Stabilized by Glycerol

Zhou

Stein

Huntington

et al. 2003

Journal of Biological Chemistry

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“…VN regulates the half-life of PAI-1, keeping its inhibitory form stable for a longer period (41,42). Several studies have demonstrated increased PAI-1 levels in severe cases of dengue.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins

Conde

Silva

Allonso

et al. 2016

J Virol

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Dengue virus (DENV) infects millions of people worldwide and is a major public health problem. DENV nonstructural protein 1 (NS1) is a conserved glycoprotein that associates with membranes and is also secreted into the plasma in DENV-infected patients. The present study describes a novel mechanism by which NS1 inhibits the terminal complement pathway. We first identified the terminal complement regulator vitronectin (VN) as a novel DENV2 NS1 binding partner by using a yeast two-hybrid system. This interaction was further assessed by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) assay. The NS1-VN complex was also detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the DENV2 NS1 protein, either by itself or by interacting with VN, hinders the formation of the membrane attack complex (MAC) and C9 polymerization. Finally, we showed that DENV2, West Nile virus (WNV), and Zika virus (ZIKV) NS1 proteins produced in mammalian cells inhibited C9 polymerization. Taken together, our results points to a role for NS1 as a terminal pathway inhibitor of the complement system. IMPORTANCE Dengue is the most important arthropod-borne viral disease nowadays and is caused by dengue virus (DENV).The flavivirus NS1 glycoprotein has been characterized functionally as a complement evasion protein that can attenuate the activation of the classical, lectin, and alternative pathways. The present study describes a novel mechanism by which DENV NS1 inhibits the terminal complement pathway. We identified the terminal complement regulator vitronectin (VN) as a novel DENV NS1 binding partner, and the NS1-VN complex was detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the NS1-VN complex inhibited membrane attack complex (MAC) formation, thus interfering with the complement terminal pathway. Interestingly, NS1 itself also inhibited MAC activity, suggesting a direct role of this protein in the inhibition process. Our findings imply a role for NS1 as a terminal pathway inhibitor of the complement system. D engue constitutes a major public health problem in tropical and subtropical countries. According to current estimates, at least 390 million cases of dengue occur annually, of which approximately 100 million are symptomatic (1). The infection is caused by dengue virus (DENV), a member of the Flaviviridae family that cocirculates in nature as four distinct antigenic serotypes (DENV1 to -4). DENV infection in humans is generally asymptomatic, but symptomatic cases can vary from a mild and self-limited fever to a potentially fatal hemorrhagic syndrome (2). The DENV genome is composed of a single positive-sense RNA that encodes a single viral polyprotein that is further processed by viral and host proteases into three structural proteins (C, prM/M, and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (3).NS1 ...

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“…2). It was named owing to its role as a checkpoint on the path to full insertion of the RCL, since it controls the opening of the lower portion of A (Hansen et al, 2001). At the core of this mechanism is a hydrogen-bonding network which (in ATIII) chiefly involves His369 on s5A and Asn217 on s3A, together with Ser79 and Ser82.…”

Section: Shutter Regionmentioning

confidence: 99%

Three-dimensional structure of a schistosome serpin revealing an unusual configuration of the helical subdomain

Granzin¹,

Huang²,

Topbaş³

et al. 2012

Acta Crystallogr D Biol Cryst

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Parasitic organisms are constantly challenged by the defence mechanisms of their respective hosts, which often depend on serine protease activities. Consequently, protease inhibitors such as those belonging to the serpin superfamily have emerged as protective elements that support the survival of the parasites. This report describes the crystal structure of ShSPI, a serpin from the trematode Schistosoma haematobium. The protein is exposed on the surface of invading cercaria as well as of adult worms, suggesting its involvement in the parasite–host interaction. While generally conforming to the well established serpin fold, the structure reveals several distinctive features, mostly concerning the helical subdomain of the protein. It is proposed that these peculiarities are related to the unique biological properties of a small serpin subfamily which is conserved among pathogenic schistosomes.

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Importance of the amino‐acid composition of the shutter region of plasminogen activator inhibitor‐1 for its transitions to latent and substrate forms

Cited by 48 publications

References 54 publications

Serpin Polymerization Is Prevented by a Hydrogen Bond Network That Is Centered on His-334 and Stabilized by Glycerol

Serpin Polymerization Is Prevented by a Hydrogen Bond Network That Is Centered on His-334 and Stabilized by Glycerol

Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins

Three-dimensional structure of a schistosome serpin revealing an unusual configuration of the helical subdomain

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