ライフサイエンスコーパス: MASP

1 MASP-1 activates MASP-2 and, moreover, inhibition of MAS

2 MASP-1 and MASP-3 are related proteases found in similar

3 MASP-1 has been shown to aid MASP-2 convertase generatio

4 MASP-1 protein was immunochemically localized to synovia

5 MASP-1 transactivates MASP-2 and, although MASP-1 also c

6 MASP-1 was recently found to be the exclusive activator

7 MASP-1 was shown to cleave high m.w. kininogen into brad

8 MASP-2 cleaves C4 releasing C4a and generating C4b, whic

9 MASP-2 deficiency also protects mice from gastrointestin

10 MASP-2 is considered as the autonomous pathway-activator

11 MASP-2 was co-purified with H-ficolin, and the purified

12 MASP-3, which does not autoactivate, is also cleaved by

13 MASPs have a modular structure consisting of an N-termin

14 g lectin (MBL)-associated serine protease-1 (MASP-1) and MASP-3 contain zymogenic FD (pro-FD), and it

15 ficolin-associated serine protease (MASP)-1, MASP-2, and MASP-3 from the MBL complex.

16 led MBL-associated serine proteases (MASP-1, MASP-2, and MASP-3).

17 ation kinetics using purified active MASP-1, MASP-2, MASP-3, as well as thrombin.

18 L or ficolins allows the formation of MASP-1-MASP-2 co-complexes.

19 tiated by the C1r/C1s (classical) and MASP-1/MASP-2 (lectin) proteases.

20 binding lectin-associated serine protease 2 (MASP-2) has been described as the essential enzyme for t

21 mplex with MBL-associated serine protease 2 (MASP-2) was able to activate the lectin pathway and depo

22 olins with MBL-associated serine protease-2 (MASP-2) and C1q with C1r and C1s.

23 binding lectin-associated serine protease-2 (MASP-2) on the mutant.

24 binding lectin-associated serine protease-2 (MASP-2), and analyzed the role of MASP-2 in two models o

25 d activate MBL-associated serine protease-2 (MASP-2).

26 nding lectin-associated serine proteinase 2 (MASP-2) is essential for LP activation, and therefore, i

27 netics using purified active MASP-1, MASP-2, MASP-3, as well as thrombin.

28 annose-binding lectin associated-protease-3 (MASP-3) is a member of the lectin pathway of the complem

29 The serum levels of ficolin-2, ficolin-3, MASP-2, ficolin-3/MASP-2 complex, C1-INH, and C4, as wel

30 Levels of MASP-2 and of the ficolin-3/MASP-2 complex were elevated (P < .0001 and .033, respec

31 s of ficolin-2, ficolin-3, MASP-2, ficolin-3/MASP-2 complex, C1-INH, and C4, as well as the extent of

32 nctional unit for complement activation is a MASP homodimer bound to two MBP trimeric subunits.

33 The role of the much more abundant MASP-1 protease was controversial.

34 entrations of the attachment receptor, ACE2, MASPs, their endogenous inhibitors (the Kunitz-type tran

35 MASP-1 activates MASP-2 and, moreover, inhibition of MASP-1 prevents auto

36 canonical inhibitor developed against active MASP-1, indicating that zymogen MASP-1 fluctuates betwee

37 , we found that lack of enzymatically active MASP-3, or complete MASP-3 deficiency, compromises the c

38 activators in resting blood; however, active MASP-3 is a very likely physiological activator.

39 ts activation kinetics using purified active MASP-1, MASP-2, MASP-3, as well as thrombin.

40 sing unique, monospecific inhibitors against MASP-1 and MASP-2, we corrected the mechanism of lectin-

41 MASP-1 has been shown to aid MASP-2 convertase generation by auxiliary C2 cleavage.

42 MASP-1 transactivates MASP-2 and, although MASP-1 also cleaves C2, MASP-2 cleaves both C4 and C2, a

43 We show that, although MASP-2 is able to autoactivate under artificial conditio

44 In this study, we demonstrate that, although MASPs do not directly form heterodimers, the addition of

45 Complexes containing both MAP-1 and MASP-1 or -3 were detected in normal human serum and pla

46 The levels of MASP-1 and MASP-1/C1-INH complexes are reduced in HAE patients comp

47 Both MASP-1 and MASP-1/C1-INH complexes are related to the degree of com

48 The level of MASP-1 and MASP-1/C1-INH complexes in HE patients correlated with t

49 functional terms, it appears that MASP-1 and MASP-2 act in a manner analogous to that of C1r and C1s

50 s recently demonstrated that both MASP-1 and MASP-2 are crucial to lectin pathway activation.

51 f the classical pathway, in which MASP-1 and MASP-2 are found together in the same MBL or ficolin com

52 We further demonstrate that MASP-1 and MASP-2 can associate in the same MBL complex, and that s

53 Combining our quantitative data, MASP-1 and MASP-2 can be ruled out as direct pro-FD activators in r

54 MBL-associated serine proteases (MASP)-1 and MASP-2 cleave C4 and C2 to generate C3 convertase.

55 Juxtaposition of MASP-1 and MASP-2 during activation must be required for transactiv

56 haelis-like complex structures of MASP-1 and MASP-2 formed with substrate-like inhibitors.

57 ur previously developed selective MASP-1 and MASP-2 inhibitors did not reduce pro-FD activation at re

58 es that binding to both truncated MASP-1 and MASP-2 proteins is defective in such mutants.

59 le cross-activation steps between MASP-1 and MASP-2 were determined.

60 MBL)-associated serine proteases, MASP-1 and MASP-2, have been thought to autoactivate when MBL/ficol

61 , monospecific inhibitors against MASP-1 and MASP-2, we corrected the mechanism of lectin-pathway act

62 mplement pathway serine proteases MASP-1 and MASP-2.

63 MASP-1 and MASP-3 are related proteases found in similar complexes.

64 It was suggested that MASP-1 and MASP-3 directly activate pro-FD; however, other experime

65 In mice, MASP-1 and MASP-3 have been reported to be central also to alternat

66 tigated the direct interactions of MAP-1 and MASP-3 with ficolin-3 and MBL using surface plasmon reso

67 y (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively).

68 unaffected by reconstitution with MASP-1 and MASP-3.

69 gene and hence deficient in both MASP-1 and MASP-3.

70 L)-associated serine protease-1 (MASP-1) and MASP-3 contain zymogenic FD (pro-FD), and it is becoming

71 lative effects of inhibiting both MASP-2 and MASP-1 have a greater effect on the lectin pathway than

72 ciated serine protease (MASP)-1, MASP-2, and MASP-3 from the MBL complex.

73 ciated serine proteases (MASP-1, MASP-2, and MASP-3).

74 o and was associated with both MASP-1/-3 and MASP-2 in plasma.

75 Both ficolin-3 and MASP-2 levels correlated inversely with the time from th

76 inhibitor blocks the active sites of C1s and MASP-2, as well as the anion-binding exosites of the enz

77 iant Amazon leech, potently inhibits C1s and MASP-2, whereas it is also a good inhibitor of MASP-1.

78 n vitro and shown to require MASP-2, C2, and MASP-1/3.

79 Mutations in C4 and MASP-2 residues at the C345C-CCP interface inhibit the i

80 are initiated by the C1r/C1s (classical) and MASP-1/MASP-2 (lectin) proteases.

81 biological properties both MAP (CsMAP34) and MASP (CsMASP1) molecules from tongue sole (Cynoglossus s

82 localization of mRNA and protein for FD and MASP-1/3 in synovial adipose tissue (SAT) and fibroblast

83 ment pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively).

84 on of immune complexes (ICs) containing anti-MASP SP IgGs in patients with different (cardiac, digest

85 perimental model suggest the utility of anti-MASP-2 antibody therapy in reperfusion injury and other

86 rized the naturally occurring 3MC-associated MASP-3 mutants and found that they all yielded enzymatic

87 olving the lectin pathway and its associated MASPs.

88 These novel TFPI1-based MASP-2 inhibitor (TFMI-2) variants are potent and select

89 of MASP-1 and the complex formation between MASP-1 and C1-INH were significantly reduced in HAE pati

90 d, we have analyzed the interactions between MASP-2, C4, C2, and their activation fragments and have

91 the possible cross-activation steps between MASP-1 and MASP-2 were determined.

92 Both MASP-1 and MASP-1/C1-INH complexes are related to the de

93 ity was confirmed in mice deficient for both MASP-2 and C4 (n=7), where the protection from postopera

94 f the MASP1 gene and hence deficient in both MASP-1 and MASP-3.

95 at the cumulative effects of inhibiting both MASP-2 and MASP-1 have a greater effect on the lectin pa

96 nvestigators recently demonstrated that both MASP-1 and MASP-2 are crucial to lectin pathway activati

97 range in vitro and was associated with both MASP-1/-3 and MASP-2 in plasma.

98 Binding studies reveal that both MASPs associate independently with rat MBP in a Ca(2+)-d

99 investigate whether activation of MASP-2 by MASP-1 occurs through PRM-driven juxtaposition on ligand

100 ch does not autoactivate, is also cleaved by MASP-1 quite efficiently.

101 C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).

102 ng that cleavage of pro-FD into mature FD by MASP-1 occurred on the CMP.

103 3 supernatants was cleaved into mature FD by MASP-1/3 in FLS supernatants.

104 ciated serine protease (MASP)-2, followed by MASP-2 autoactivation and cleavage of C4 and C2 generati

105 The perovskite films produced by MASP exhibit excellent optoelectronic properties with ef

106 nal lectin pathway, which can be restored by MASP-1, implying that this component is crucial for comp

107 This C4-bypass MASP-2 activity was confirmed in mice deficient for both

108 MASP-2 and, although MASP-1 also cleaves C2, MASP-2 cleaves both C4 and C2, allowing formation of the

109 s of the 203-kDa human C4 and the 245-kDa C4.MASP-2 substrate.enzyme complex.

110 We propose that the C4b.MASP-2 interaction favors attachment of C4b near to the

111 their activation fragments and have compared MASP-2-catalyzed cleavage of C4b2 and C2.

112 of enzymatically active MASP-3, or complete MASP-3 deficiency, compromises the conversion of pro-FD

113 to autoactivate under artificial conditions, MASP-1 dramatically increases lectin pathway activity at

114 Combining our quantitative data, MASP-1 and MASP-2 can be ruled out as direct pro-FD acti

115 as restored when rMASP-1 was added to either MASP-1/-3 KO sera or rhMBL.

116 d MASP-1 serum concentrations and endogenous MASP-1/C1-INH complex levels in 128 HAE patients and 100

117 We have also engineered MASP binding into a pulmonary surfactant protein (SP-A),

118 Relatively high levels of pre-existing MASP-1/C1-INH complexes were observed in normal serum, a

119 t, while also highlighting that there exists MASP-3-independent pro-FD maturation in 3MC patients.

120 d with H-ficolin, and the purified H-ficolin.MASP-2 complex could activate complement as measured by

121 een thought to autoactivate when MBL/ficolin.MASP complexes bind to pathogens triggering the compleme

122 is crucial for the activation of MBL/ficolin.MASP complexes, and in the proenzymic phase zymogen MASP

123 However, the molecular basis for MASP-3 function remains to be understood.

124 n MBL conserved lysine residue essential for MASP binding (K55) abolished binding to soluble CR1 and

125 Analogous mutants were made for MASP-2, and rate constants of the autoactivation steps a

126 e AP activity is still observed in sera from MASP-1/3-deficient Malpuech-Michels-Mingarelli-Carnevale

127 coated with anti-collagen mAb and serum from MASP-1/3(-/-) mice as a source of factor B, pro-FD in 3T

128 Here, we present our third-generation MASP-2 inhibitors that were developed based on a human i

129 meostasis of epithelial barrier tissues; how MASPs are activated in mature epithelia is unknown.

130 n this investigation, we identified immature MASP proteins containing the MASP SP in EVs secreted by

131 In MASP-2, an exosite located within the CCP domains recogn

132 Mutations in MASP-3 have recently been found to be associated with Ca

133 (control group), WT grafts transplanted into MASP-2-deficient recipients (n=7) showed significantly b

134 In a model of transient myocardial IRI, MASP-2-deficient mice had significantly smaller infarct

135 sting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed.

136 than the zymogen state is default in lectin.MASP complexes and must be inhibited through additional

137 exclusive or predominant expression of major MASPs in specific human organs suggests a direct role of

138 MBL-deficient individuals when exogenous MBL-MASP was added.

139 th and without the addition of exogenous MBL-MASP.

140 s disease patients have an impairment in MBL-MASP functional activity and that this defect is associa

141 icantly correlated with an impairment in MBL-MASP functional activity.

142 iologic (24 microg/ml) concentrations of MBL-MASP partially overcame the effects of inhibitors (57% k

143 ctin-mannose-associated serine protease (MBL-MASP) functional activity in Crohn's disease patients.

144 We conclude that MBL-MASP makes a major contribution to complement-mediated h

145 Preopsonization with MBL-MASP at concentrations as low as 0.03 microg/ml resulted

146 epleted serum (MBLdS) reconstituted with MBL-MASP before incubation with organisms (postopsonization)

147 pha(2)-macroglobulin added together with MBL-MASP, all at physiologic concentrations before adding MB

148 gnificant increases in phagocytosis with MBL-MASPs that were independent of complement activation.

149 attachment of C4b near to the activating MBL.MASP complex on the bacterial surface so that, following

150 blood aggregation demonstrated increased MBL/MASP complex-dependent platelet aggregation.

151 n together, these findings indicate that MBL/MASP complexes, and specifically MASP-1, play a key role

152 ce, suggesting a significant role of the MBL/MASP complex for in vivo coagulation.

153 In vitro, MBL/MASP complexes were captured on mannan-coated plates, an

154 We measured MASP-1 serum concentrations and endogenous MASP-1/C1-INH

155 In mice, MASP-1 and MASP-3 have been reported to be central also

156 We evolved a pair of monospecific MASP inhibitors.

157 higher, and the autocatalytic activation of MASP-1 is about 140-fold faster than those of MASP-2.

158 pted us to investigate whether activation of MASP-2 by MASP-1 occurs through PRM-driven juxtaposition

159 ical conditions through direct activation of MASP-2.

160 ently found to be the exclusive activator of MASP-2 under physiological conditions, yet the predomina

161 the absolute requirement for the activity of MASP-1 protein in autoimmune-associated inflammatory tis

162 Analysis of MASP binding by rat MBP containing naturally occurring m

163 In summary, autoactivation of MASP-1 is crucial for the activation of MBL/ficolin.MASP

164 ibition of MASP-1 prevents autoactivation of MASP-2.

165 In C1q(-/-) TM mice, colocalization of MASP-2 and C3 in both the glomeruli and tubules indicate

166 t, not simply by brute force displacement of MASP-2 from MBL or ficolins, but by disruption of co-com

167 usion (IR) injury, we assessed the effect of MASP-2 deficiency in an isogenic mouse model of renal tr

168 The therapeutic effects of MASP-2 inhibition in this experimental model suggest the

169 P was not sufficient, because elimination of MASP, but not C1q, prevented TER reduction.

170 n of MBL or ficolins allows the formation of MASP-1-MASP-2 co-complexes.

171 ogether, these insights into the function of MASP-3 reveal how a mutation in this enzyme causes it to

172 ously developed the first two generations of MASP-2 inhibitors by in vitro evolution of two unrelated

173 ctivates MASP-2 and, moreover, inhibition of MASP-1 prevents autoactivation of MASP-2.

174 SP-2, whereas it is also a good inhibitor of MASP-1.

175 ntestinal IRI, as do mAb-based inhibitors of MASP-2.

176 Juxtaposition of MASP-1 and MASP-2 during activation must be required for

177 The level of MASP-1 and MASP-1/C1-INH complexes in HE patients correl

178 The levels of MASP-1 and MASP-1/C1-INH complexes are reduced in HAE pa

179 , and we found that both the serum levels of MASP-1 and the complex formation between MASP-1 and C1-I

180 Levels of MASP-2 and of the ficolin-3/MASP-2 complex were elevated

181 In order to investigate the mechanisms of MASP activation by MBP, the cDNAs of rat MASP-1 and -2 h

182 e of the zymogen form of the G666E mutant of MASP-3.

183 However, the necessity of MASP-3 for pro-FD cleavage has been questioned, because

184 binding to mannan or DNA in the presence of MASP-2, the CL-L1-CL-K1 complex mediated deposition of C

185 sized that MASP-1 levels and the quantity of MASP-1/C1-INH complexes might be associated with differe

186 The zymogen autoactivation rate of MASP-1 is approximately 3000-fold higher, and the autoca

187 rotease-2 (MASP-2), and analyzed the role of MASP-2 in two models of postischemic reperfusion injury

188 In accordance with the key role of MASP-2, the MASP-2 inhibitor completely blocks the lecti

189 ings reveal a new route for the secretion of MASP proteins in T. cruzi, which uses EVs as vehicles fo

190 esidue into the P2 of the activation site of MASP-3, a protein with similar domain structure to C1s t

191 FLS were the main source of MASP-1/3 mRNA and protein.

192 we characterize the substrate specificity of MASP-3 by screening against a combinatorial peptide subs

193 The autoactivation steps of MASP-1 were separately quantified using these mutants an

194 e first Michaelis-like complex structures of MASP-1 and MASP-2 formed with substrate-like inhibitors.

195 ASP-1 is about 140-fold faster than those of MASP-2.

196 providing a scenario for transactivation of MASP-2.

197 g does not directly escort the transition of MASP from zymogen to active enzyme in the PRM/MASP compl

198 Autoactivation of MASPs occurs in two steps: 1) zymogen autoactivation, wh

199 A common feature of MASPs is the presence of two conserved regions: an N-ter

200 We decided to clarify the involvement of MASPs in pro-FD activation in normal, as opposed to defi

201 The AP in mice is dependent on MASP-1/3 cleavage of pro-factor D (pro-FD) into mature f

202 serum, MASP-2 activation strictly depends on MASP-1.

203 recombinant MASPs were added to plasma, only MASP-3 could reduce the half-life of pro-FD.

204 -), or MBL-C(-/-) sera; however, MBL-null or MASP-1/-3 KO mouse sera demonstrated significantly decre

205 , the MASP-2 inhibitor, which is also a poor MASP-3 inhibitor, slowed down the activation.

206 fective meniscus-assisted solution printing (MASP) strategy to yield large-grained dense perovskite f

207 mplex activation occurs between discrete PRM/MASP complexes.

208 PRM/MASP complex; rather, clustering of PRM/MASP complexes directly causes activation.

209 ASP from zymogen to active enzyme in the PRM/MASP complex; rather, clustering of PRM/MASP complexes d

210 Proenzyme MASP-1 R448Q readily cleaves synthetic substrates, and i

211 Moreover, both activated and proenzyme MASP-1 can effectively cleave proenzyme MASP-2.

212 zyme MASP-1 can effectively cleave proenzyme MASP-2.

213 ructure of the catalytic region of proenzyme MASP-1 R448Q was solved at 2.5 A.

214 nts, we demonstrated that a stable proenzyme MASP-1 variant (R448Q) cleaved the inactive, catalytic s

215 ectin complement pathway-associated protease MASP-2 to trigger complement deposition.

216 in (MAP) and MBL associated serine protease (MASP) are scarcely investigated.

217 or near the MBL-associated serine protease (MASP) binding site in the collagen stalks of MBL and L-f

218 aces MBL/ficolin-associated serine protease (MASP)-1, MASP-2, and MASP-3 from the MBL complex.

219 BL)-null and MBL-associated serine protease (MASP)-1/-3 knockout (KO) mice had significantly decrease

220 e-binding lectin-associated serine protease (MASP)-1/3(-/-) mice contains pro-FD and has markedly red

221 e-binding lectin-associated serine protease (MASP)-2 has been considered the autonomous initiator of

222 complex with MBL-associated serine protease (MASP)-2, followed by MASP-2 autoactivation and cleavage

223 tor complex, MBL-associated serine protease (MASP)-3/collectin-L1/K1 hetero-oligomer, which impacts c

224 e lectin complement pathway serine proteases MASP-1 and MASP-2.

225 in complex with associated serine proteases MASP-1, -2, and -3 and the non-enzymatic small MBL assoc

226 ed with the MBL-associated serine proteases (MASP)-1 and MASP-2 cleave C4 and C2 to generate C3 conve

227 plexes with MBL-associated serine proteases (MASP-1, -2, and -3) and MBL-associated proteins (MAp19 a

228 f so-called MBL-associated serine proteases (MASP-1, MASP-2, and MASP-3).

229 in/collectin-11-associated serine proteases (MASPs) in binding to MBL and the ficolins.

230 Membrane-anchored serine proteases (MASPs) play critical roles in the development and homeos

231 plexed with MBL-associated serine proteases (MASPs) to N. gonorrhoeae was achieved at a concentration

232 -binding lectin-associated serine proteases (MASPs) with affinities in the nM range in vitro and was

233 omplex with MBP-associated serine proteases (MASPs), which become activated upon engagement of a targ

234 -binding lectin-associated serine proteases (MASPs).

235 -binding lectin-associated serine proteases (MASPs).

236 ng lectin (MBL)-associated serine proteases, MASP-1 and MASP-2, have been thought to autoactivate whe

237 copies) of mucin-associated surface protein (MASP) genes.

238 eral membrane-associated serine proteinases (MASPs), in synergy with or in place of TMPRSS2, contribu

239 luding the MASP multigene family of proteins MASPs are specific to this parasite and characterized by

240 ay to yield inhibitors against human and rat MASP-2.

241 of MASP activation by MBP, the cDNAs of rat MASP-1 and -2 have been isolated, and portions encompass

242 When recombinant MASPs were added to plasma, only MASP-3 could reduce the

243 s demonstrated in vitro and shown to require MASP-2, C2, and MASP-1/3.

244 The 1.28 A resolution MASP-2 structure reveals significant plasticity of the p

245 This robust MASP strategy may in principle be easily extended to cra

246 Our previously developed selective MASP-1 and MASP-2 inhibitors did not reduce pro-FD activ

247 In normal human serum, MASP-2 activation strictly depends on MASP-1.

248 oligomeric forms of MBL carry only a single MASP homodimer.

249 te that MBL/MASP complexes, and specifically MASP-1, play a key role in thrombus formation in vitro a

250 udy were to determine the cells synthesizing MASP-1/3 and pro-FD in synovial tissue.

251 Hence, in functional terms, it appears that MASP-1 and MASP-2 act in a manner analogous to that of C

252 We further demonstrate that MASP-1 and MASP-2 can associate in the same MBL complex,

253 Furthermore we demonstrated that MASP-1 produces 60% of C2a responsible for C3 convertase

254 inhibitor does the same, demonstrating that MASP-1 is not an auxiliary but an essential pathway comp

255 In summary, our observations emphasize that MASP-3 acts as an important maturase in the AP of comple

256 FD (pro-FD), and it is becoming evident that MASP-3 is implicated in pro-FD maturation.

257 bradykinin; therefore, we hypothesized that MASP-1 levels and the quantity of MASP-1/C1-INH complexe

258 In conclusion, we show that MASP-1/C1-INH complexes circulate in normal human blood.

259 These results suggest that MASP-1 may exert a previously unrecognized role in the p

260 It was suggested that MASP-1 and MASP-3 directly activate pro-FD; however, oth

261 Altogether, these findings suggest that MASPs can associate in various combinations and bring ne

262 The MASP multigene family is specific to T. cruzi, accountin

263 accordance with the key role of MASP-2, the MASP-2 inhibitor completely blocks the lectin pathway ac

264 e presence of an immune response against the MASP C-term region.

265 Moreover, purified EVs as well as the MASP SP inhibit the action of the complement system and

266 In contrast, at very high concentration, the MASP-2 inhibitor, which is also a poor MASP-3 inhibitor,

267 tified immature MASP proteins containing the MASP SP in EVs secreted by the infective forms of the pa

268 Importantly, the MASP-1 inhibitor does the same, demonstrating that MASP-

269 with different protein cargoes including the MASP multigene family of proteins MASPs are specific to

270 -1 also enables modeling and assembly of the MASP-1 molecule in its entirety.

271 The crystal structure of the MASP-2 CUB1-EGF-CUB2 dimer reveals an elongated structur

272 This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage

273 in which the position and orientation of the MASP-binding sites have been changed.

274 phenotype was preserved, indicating that the MASP-2-mediated damage was independent of C4 activation.

275 thway of blood coagulation transactivate the MASP matriptase, thus connecting coagulation initiation

276 When H-ficolin binds to microorganisms the MASPs are activated, which in turn activate the compleme

277 involved in heterocomplex formation with the MASPs thereby breaking the stoichiometry of the activati

278 we found that MAP-1 competes with all three MASPs for ligand binding and is able to mediate a strong

279 ury and indicates that injury occurs through MASP-2-dependent activation events independent of C4.

280 Following cleavage of C4, C4b still binds to MASP-2 (KD approximately 0.6 microM) and dissociates rel

281 When C4 binds to MASP-2, substantial conformational changes in C4 are ind

282 activation via its ability to recruit MBL to MASP, and other hand as a modulator of immune cell activ

283 transmits conformational changes from MBP to MASP that allow activation of its protease activity.

284 MASP-1 transactivates MASP-2 and, although MASP-1 also cleaves C2, MASP-2 clea

285 ncy indicates that binding to both truncated MASP-1 and MASP-2 proteins is defective in such mutants.

286 ified proteins indicates that each truncated MASP is a Ca(2+)-independent homodimer in solution, in w

287 The biophysical properties of the truncated MASPs indicate that the interactions with MBP leading to

288 C patient carrying a previously unidentified MASP-3 G665S mutation prompted us to develop an analytic

289 Using MASP-3-depleted human serum, serum from 3MC patients, an

290 enzymes to be efficient activators, whereas MASP proenzymes lacked such activity.

291 for disease induction, to determine whether MASP-1/3 are required in vivo for the development of tis

292 lels that of the classical pathway, in which MASP-1 and MASP-2 are found together in the same MBL or

293 d as the autonomous pathway-activator, while MASP-1 is considered as an auxiliary component.

294 We found that MAp44 competed with MASP-3 for pattern recognition molecule interaction, and

295 ent activity is introduced concurrently with MASP binding in SP-A but is uncontrolled and occurs even

296 in, as shown by competition experiments with MASP-3.

297 nal failure was no greater than in mice with MASP-2 deficiency alone.

298 ly, and is unaffected by reconstitution with MASP-1 and MASP-3.

299 eric complexes with CL-L1 that interact with MASPs and can mediate complement activation.

300 mplexes, and in the proenzymic phase zymogen MASP-1 controls the process.

301 ainst active MASP-1, indicating that zymogen MASP-1 fluctuates between an inactive and an active-like