The 2.1-Å Crystal Structure of Native Neuroserpin Reveals Unique Structural Elements That Contribute to Conformational Instability

Takehara, Shoichiro; Onda, Maki; Zhang, Juan; Nishiyama, Masahide; Yang, Xiao-Yan; Mikami, Bunzo; Lomas, David A.

doi:10.1016/j.jmb.2009.03.007

Cited by 41 publications

(79 citation statements)

References 43 publications

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“…This differential effect of sc-tPA and tc-tPA on NMDAR, in addition to their previously reported differential kinetics of inhibition by NS, 35,36 emphasizes a subtle control of tPA function in the brain. In view of these data, we should reconsider part of the tPA mechanisms reported to influence the brain functions and dysfunctions.…”

Section: Discussionmentioning

confidence: 50%

“…Indeed, Barker-Carlson and collaborators demonstrated that reversible sc-tPA-NS complexes were more stable than those formed with tc-tPA. 35,36 No loss of sequence takes place during the conversion of sc-tPA into tc-tPA. The selective action of the single-chain form of tPA could be explained by the previous demonstration that tPA interacts with the NMDA receptor through two sites.…”

Section: Discussionmentioning

confidence: 99%

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Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity

et al. 2012

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity

et al. 2012

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“…Six mutations have now been described that underlie FENIB [48][49][50]. We have assessed a range of mutants of different severity in purified recombinant protein, cell, fly, worm and mouse models of disease [48,[51][52][53][54][55][56][57]. The data show a direct relationship between the severity of the mutation, the rate of polymer formation and the severity of the associated dementia.…”

Section: Polymers and The Serpinopathiesmentioning

confidence: 99%

Update on alpha-1 antitrypsin deficiency: New therapies

Lomas

Hurst

Gooptu

2016

Journal of Hepatology

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α 1 -antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α 1 -antitrypsin within the endoplasmic reticulum of hepatocytes. The retention of mutant protein causes hepatic damage and cirrhosis whilst the lack of an important circulating protease inhibitor predisposes the individuals with severe α 1 -antitrypsin deficiency to early onset emphysema. Our work over the past 25 years has led to new paradigms for the liver and lung disease associated with α 1 -antitrypsin deficiency. We review here the molecular pathology of the cirrhosis and emphysema associated with α 1 -antitrypsin deficiency and show how an understanding of this condition provided the paradigm for a wider group of disorders that we have termed the serpinopathies.The detailed understanding of the pathobiology of α 1 -antitrypsin deficiency has identified important disease mechanisms to target. As a result, several novel parallel and complementary therapeutic approaches are in development with some now in clinical trials.We provide an overview of these new therapies for the liver and lung disease associated with α 1 -antitrypsin deficiency.

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“…Our recent crystal structure of neuroserpin 37 allowed us to identify His119 and His138 as other likely candidates (Fig. 3).…”

Section: Other Histidines Are Involved In Neuroserpin Polymerizationmentioning

confidence: 99%

“…3(A)]. 37 Indeed, the crystal structures of both a 1 -antitrypsin (1QLP) 40 and antithrombin (1E04) 41 show that His334 forms two hydrogen bonds with Asn186 and Ser53 at neutral pH. However, at acidic pH the hydrogen bond between His334 and Ser53 is broken by protonation of His334, and so a 1 -antitrypsin and antithrombin become unstable.…”

Section: Other Histidines Are Involved In Neuroserpin Polymerizationmentioning

confidence: 99%

pH‐dependent stability of neuroserpin is mediated by histidines 119 and 138; Implications for the control of β‐sheet A and polymerization

et al. 2010

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Neuroserpin is a member of the serpin superfamily. Point mutations in the neuroserpin gene underlie the autosomal dominant dementia, familial encephalopathy with neuroserpin inclusion bodies. This is characterized by the retention of ordered polymers of neuroserpin within the endoplasmic reticulum of neurons. pH has been shown to affect the propensity of several serpins to form polymers. In particular, low pH favors the formation of polymers of both a 1 -antitrypsin and antithrombin. We report here opposite effects in neuroserpin, with a striking resistance to polymer formation at acidic pH. Mutation of specific histidine residues showed that this effect is not attributable to the shutter domain histidine as would be predicted by analogy with other serpins. Indeed, mutation of the shutter domain His338 decreased neuroserpin stability but had no effect on the pH dependence of polymerization when compared with the wild-type protein.In contrast, mutation of His119 or His138 reduced the polymerization of neuroserpin at both acidic and neutral pH. These residues are at the lower pole of neuroserpin and provide a novel mechanism to control the opening of b-sheet A and hence polymerization. This mechanism is likely to have evolved to protect neuroserpin from the acidic environment of the secretory granules.

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The 2.1-Å Crystal Structure of Native Neuroserpin Reveals Unique Structural Elements That Contribute to Conformational Instability

Cited by 41 publications

References 43 publications

Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity

Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity

Update on alpha-1 antitrypsin deficiency: New therapies

pH‐dependent stability of neuroserpin is mediated by histidines 119 and 138; Implications for the control of β‐sheet A and polymerization

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