Human Neuroserpin: Structure and Time-Dependent Inhibition

Ricagno, Stéfano; Caccia, Sonia; Sorrentino, Graziella; Antonini, Giovanni; Bolognesi, Martino

doi:10.1016/j.jmb.2009.02.056

Cited by 40 publications

(90 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4,44 The crystal structure of the native neuroserpin monomer shows that His119 can form a hydrogen bond with Asp327 when the imidazole ring is protonated at acidic pH. 37 Another crystal structure of native neuroserpin reported by Ricagno et al 42 shows that His119 can also form a hydrogen bond with Glu122 [ Fig. 3(B)].…”

Section: Other Histidines Are Involved In Neuroserpin Polymerizationmentioning

confidence: 99%

“…3(B)] where there is no histidine in a 1 -antitrypsin and antithrombin. 37,[40][41][42] Interestingly, the two His residues are very close to a hydrophobic pocket composed of Val114, Val120, Leu125, and Val136 between strand 1A and helix E [ Fig. 3(B)].…”

Section: Other Histidines Are Involved In Neuroserpin Polymerizationmentioning

confidence: 99%

“…The crystal structure of the cleaved form of neuroserpin simulates a situation in which the side chain of His119 moves away from the two acidic residues. 42 In cleaved neuroserpin, His119 3(C)]. Polymerization of His119Gln at pH 7.0 is likely to be due to a destabilization of His138 or the sum of effects from other His residues.…”

Section: Other Histidines Are Involved In Neuroserpin Polymerizationmentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

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.

show abstract

Section: Other Histidines Are Involved In Neuroserpin Polymerizationmentioning

confidence: 99%

Section: Other Histidines Are Involved In Neuroserpin Polymerizationmentioning

confidence: 99%

Section: Other Histidines Are Involved In Neuroserpin Polymerizationmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

show abstract

“…The 3-D structure of uncleaved, native neuroserpin was determined by X-ray diffraction (3F5N, 3F02) and is shown in Fig. 12 [180]. It contains the expected elements of the core structure of serpins: three b-sheets (shown in red, green, and yellow), nine a-helices (in grey), and the exposed RCL (in blue).…”

Section: Plasminogen Activator Inhibitorsmentioning

confidence: 99%

The plasmin–antiplasmin system: structural and functional aspects

Schaller

Gerber

2010

Cell. Mol. Life Sci.

141

130

View full text Add to dashboard Cite

The plasmin-antiplasmin system plays a key role in blood coagulation and fibrinolysis. Plasmin and α(2)-antiplasmin are primarily responsible for a controlled and regulated dissolution of the fibrin polymers into soluble fragments. However, besides plasmin(ogen) and α(2)-antiplasmin the system contains a series of specific activators and inhibitors. The main physiological activators of plasminogen are tissue-type plasminogen activator, which is mainly involved in the dissolution of the fibrin polymers by plasmin, and urokinase-type plasminogen activator, which is primarily responsible for the generation of plasmin activity in the intercellular space. Both activators are multidomain serine proteases. Besides the main physiological inhibitor α(2)-antiplasmin, the plasmin-antiplasmin system is also regulated by the general protease inhibitor α(2)-macroglobulin, a member of the protease inhibitor I39 family. The activity of the plasminogen activators is primarily regulated by the plasminogen activator inhibitors 1 and 2, members of the serine protease inhibitor superfamily.

show abstract

“…These proteins inhibit activity of proteases by a conserved pathway using a profound conformational change [1][2][3]. Among all PIs, serine protease inhibitors are the largest and most widely distributed superfamily of PIs [4][5][6].…”

Section: Introductionmentioning

confidence: 99%