Abstract 2008 The Latent State of Protease Domain in Coagulation Factor IXa Discovered by X-Ray Crystallography Provides Exosite-Mediated Allosteric Control of Blood Clotting Article Swipe

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Vladimir N. Kolyadko , Juliana M. Layzer , Bruce A. Sullenger , Sriram Krishnaswamy ·

YOU? · · 2024 · Open Access · · DOI: https://doi.org/10.1016/j.jbc.2024.106217

Background: Serine proteases of blood coagulation are specifically modulated by cofactors to enable timely hemostatic response without inducing thrombosis. Coagulation factor IXa, a protease component of the enzymic complex called 'intrinsic Xase', is an enigmatic enzyme due to extremely low catalytic activity in the free state. Although its protease domain has the same architecture of an activated trypsin-like protease as homologous coagulation enzymes thrombin and factor Xa, the mechanism of factor IXa function remains elusive. Objective: to study the conformational ensemble of factor IXa and reveal structural transitions enabling the gain and loss of the catalytic function. Methods: X-ray crystallography was used to resolve the structures of recombinant human factor IXa (S195A) with truncated N-terminal domains that was purified from stable AV12 cell clones. Binding affinity to biotinylated anti-IXa aptamer was measured by bio-layer interferometry in conditions with negligible mass-transport effects. Affinity of the IXa-aptamer interaction in solution was measured by fluorescence anisotropy. Active site function was assessed by kinetic measurements of fluorogenic substrate cleavage and by formation of covalent complex with antithrombin. Results: Structure of the apo-enzyme is resolved at 1.9 Å. Co-crystal structure with anti-IXa RNA aptamer having anticoagulant effect is resolved at 2.6 Å. In the apo-state, the active site of factor IXa is found in the latent conformation, with W215 side chain interfering with the entrance into S1 substrate-binding pocket. In comparison, structures of apo- thrombin and factor Xa both exhibit the open conformation of the S1 pocket, which explains a uniquely low catalytic turnover by IXa in comparison to homologous proteases. The co-crystal structure of IXa-aptamer complex shows that the aptamer does not occlude the active site and binds the protease domain in the remote exosite region, which was previously implicated in binding cofactor VIIIa and anticoagulant drug heparin. The structure shows that residues K132, L162, R165, R233 of factor IXa are important for the interaction with aptamer. Together with previous mutagenesis data, this indicates the determinants of sub-nanomolar affinity and exclusive specificity of the aptamer to IXa. Comparison of the active site conformations in apo- vs. aptamer-bound vs. substrate-bound states of factor IXa demonstrates the structural mechanism explaining the inhibitory action of the aptamer. The RNA aptamer acts allosterically by causing a 7-Å displacement of W215 that leads to the closure of S1 pocket. These structural rearrangements correlate with the aptamer-mediated inhibition of both substrate cleavage and active site-mediated interaction with antithrombin. Conclusions: This work provides the first structural evidence of allosteric control of enzymatic activity in factor IXa. The molecular surface occupied by RNA aptamer reveals an important exosite for the specific recognition and regulation of the enzymic complex assembly and catalysis. Supported by the known exosite mutations causing either bleeding or thrombotic phenotype, these findings suggest the importance of the exosite to allosterically modulate active site function of factor IXa and control the hemostatic balance. The work was supported by grant P01HL139420 from the NHLBI to S.K. and B.A.S. X-ray diffraction data were collected at the 17-ID-1 beamline at the NSLS II, a U.S. DOE Office of Science User Facility and the NE-CAT 24-ID-C beamline funded by NIH grant GM103403 with a Pilatus 6M detector funded by a NIH-ORIP HEI grant (RR029205).

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Factor IXa Allosteric regulation Coagulation Factor IX Blood clotting Factor X Chemistry Crystallography Biochemistry Biology Medicine Enzyme Internal medicine Thrombin Platelet Immunology

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Type: article
Language: en
Landing Page: https://doi.org/10.1016/j.jbc.2024.106217
PDF: http://www.jbc.org/article/S0021925824005933/pdf
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Title: Abstract 2008 The Latent State of Protease Domain in Coagulation Factor IXa Discovered by X-Ray Crystallography Provides Exosite-Mediated Allosteric Control of Blood Clotting

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Publication year: 2024

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Publication date: 2024-03-01

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Authors: Vladimir N. Kolyadko, Juliana M. Layzer, Bruce A. Sullenger, Sriram Krishnaswamy

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Concepts: Factor IXa, Allosteric regulation, Coagulation, Factor IX, Blood clotting, Factor X, Chemistry, Crystallography, Biochemistry, Biology, Medicine, Enzyme, Internal medicine, Thrombin, Platelet, Immunology

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primary_location.is_accepted	True
primary_location.is_published	True
primary_location.raw_source_name	Journal of Biological Chemistry
primary_location.landing_page_url	https://doi.org/10.1016/j.jbc.2024.106217
publication_date	2024-03-01
publication_year	2024
referenced_works_count	0
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abstract_inverted_index.6M	521
abstract_inverted_index.In	197, 224
abstract_inverted_index.S1	221, 240, 378
abstract_inverted_index.Xa	232
abstract_inverted_index.an	33, 55, 423
abstract_inverted_index.as	59
abstract_inverted_index.at	180, 194, 492, 496
abstract_inverted_index.by	9, 132, 150, 158, 166, 249, 365, 419, 440, 477, 514, 524
abstract_inverted_index.in	42, 135, 146, 208, 251, 277, 286, 339, 412
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abstract_inverted_index.or	448
abstract_inverted_index.to	11, 37, 76, 102, 126, 253, 331, 374, 459, 483
abstract_inverted_index.1.9	181
abstract_inverted_index.2.6	195
abstract_inverted_index.DOE	502
abstract_inverted_index.HEI	527
abstract_inverted_index.II,	499
abstract_inverted_index.IXa	71, 83, 110, 205, 250, 305, 348, 467
abstract_inverted_index.NIH	515
abstract_inverted_index.RNA	187, 361, 420
abstract_inverted_index.The	256, 294, 360, 415, 473
abstract_inverted_index.Xa,	66
abstract_inverted_index.and	64, 84, 91, 165, 230, 272, 290, 325, 392, 430, 437, 468, 485, 508
abstract_inverted_index.are	6, 306
abstract_inverted_index.due	36
abstract_inverted_index.for	308, 426
abstract_inverted_index.has	50
abstract_inverted_index.its	47
abstract_inverted_index.low	39, 246
abstract_inverted_index.not	267
abstract_inverted_index.the	26, 43, 51, 67, 78, 89, 94, 104, 143, 176, 198, 200, 209, 218, 235, 239, 264, 269, 274, 278, 309, 320, 329, 335, 350, 354, 358, 375, 385, 402, 427, 433, 441, 454, 457, 470, 481, 493, 497, 509
abstract_inverted_index.vs.	341, 343
abstract_inverted_index.was	100, 117, 130, 148, 156, 283, 475
abstract_inverted_index.Å.	182, 196
abstract_inverted_index.7-Å	368
abstract_inverted_index.AV12	121
abstract_inverted_index.IXa,	21
abstract_inverted_index.IXa.	332, 414
abstract_inverted_index.NSLS	498
abstract_inverted_index.R233	302
abstract_inverted_index.S.K.	484
abstract_inverted_index.This	399
abstract_inverted_index.U.S.	501
abstract_inverted_index.User	506
abstract_inverted_index.W215	213, 371
abstract_inverted_index.acts	363
abstract_inverted_index.apo-	228, 340
abstract_inverted_index.both	233, 389
abstract_inverted_index.cell	122
abstract_inverted_index.data	489
abstract_inverted_index.does	266
abstract_inverted_index.drug	292
abstract_inverted_index.free	44
abstract_inverted_index.from	119, 480
abstract_inverted_index.gain	90
abstract_inverted_index.into	220
abstract_inverted_index.loss	92
abstract_inverted_index.open	236
abstract_inverted_index.same	52
abstract_inverted_index.side	214
abstract_inverted_index.site	154, 202, 271, 337, 463
abstract_inverted_index.that	116, 263, 297, 372
abstract_inverted_index.this	318
abstract_inverted_index.used	101
abstract_inverted_index.were	490
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abstract_inverted_index.work	400, 474
abstract_inverted_index.K132,	299
abstract_inverted_index.L162,	300
abstract_inverted_index.NHLBI	482
abstract_inverted_index.R165,	301
abstract_inverted_index.These	380
abstract_inverted_index.VIIIa	289
abstract_inverted_index.X-ray	98, 487
abstract_inverted_index.binds	273
abstract_inverted_index.blood	4
abstract_inverted_index.chain	215
abstract_inverted_index.data,	317
abstract_inverted_index.first	403
abstract_inverted_index.found	207
abstract_inverted_index.grant	478, 516, 528
abstract_inverted_index.human	108
abstract_inverted_index.known	442
abstract_inverted_index.leads	373
abstract_inverted_index.shows	262, 296
abstract_inverted_index.study	77
abstract_inverted_index.these	451
abstract_inverted_index.which	242, 282
abstract_inverted_index.Active	153
abstract_inverted_index.B.A.S.	486
abstract_inverted_index.NE-CAT	510
abstract_inverted_index.Office	503
abstract_inverted_index.Serine	1
abstract_inverted_index.Xase',	31
abstract_inverted_index.action	356
abstract_inverted_index.active	201, 270, 336, 393, 462
abstract_inverted_index.called	29
abstract_inverted_index.domain	49, 276
abstract_inverted_index.effect	191
abstract_inverted_index.either	446
abstract_inverted_index.enable	12
abstract_inverted_index.enzyme	35
abstract_inverted_index.factor	20, 65, 70, 82, 109, 204, 231, 304, 347, 413, 466
abstract_inverted_index.funded	513, 523
abstract_inverted_index.having	189
abstract_inverted_index.latent	210
abstract_inverted_index.remote	279
abstract_inverted_index.reveal	85
abstract_inverted_index.stable	120
abstract_inverted_index.state.	45
abstract_inverted_index.states	345
abstract_inverted_index.timely	13
abstract_inverted_index.(S195A)	111
abstract_inverted_index.17-ID-1	494
abstract_inverted_index.24-ID-C	511
abstract_inverted_index.Binding	124
abstract_inverted_index.Pilatus	520
abstract_inverted_index.Science	505
abstract_inverted_index.aptamer	129, 188, 265, 330, 362, 421
abstract_inverted_index.binding	287
abstract_inverted_index.causing	366, 445
abstract_inverted_index.clones.	123
abstract_inverted_index.closure	376
abstract_inverted_index.complex	28, 170, 261, 435
abstract_inverted_index.control	408, 469
abstract_inverted_index.domains	115
abstract_inverted_index.enzymes	62
abstract_inverted_index.enzymic	27, 434
abstract_inverted_index.exhibit	234
abstract_inverted_index.exosite	280, 425, 443, 458
abstract_inverted_index.kinetic	159
abstract_inverted_index.occlude	268
abstract_inverted_index.pocket,	241
abstract_inverted_index.pocket.	223, 379
abstract_inverted_index.region,	281
abstract_inverted_index.remains	73
abstract_inverted_index.resolve	103
abstract_inverted_index.reveals	422
abstract_inverted_index.suggest	453
abstract_inverted_index.surface	417
abstract_inverted_index.without	16
abstract_inverted_index.Affinity	141
abstract_inverted_index.Although	46
abstract_inverted_index.Facility	507
abstract_inverted_index.GM103403	517
abstract_inverted_index.Methods:	97
abstract_inverted_index.NIH-ORIP	526
abstract_inverted_index.Results:	173
abstract_inverted_index.Together	313
abstract_inverted_index.activity	41, 411
abstract_inverted_index.affinity	125, 324
abstract_inverted_index.anti-IXa	128, 186
abstract_inverted_index.aptamer.	312, 359
abstract_inverted_index.assembly	436
abstract_inverted_index.assessed	157
abstract_inverted_index.balance.	472
abstract_inverted_index.beamline	495, 512
abstract_inverted_index.bleeding	447
abstract_inverted_index.cleavage	164, 391
abstract_inverted_index.cofactor	288
abstract_inverted_index.covalent	169
abstract_inverted_index.detector	522
abstract_inverted_index.effects.	140
abstract_inverted_index.elusive.	74
abstract_inverted_index.enabling	88
abstract_inverted_index.ensemble	80
abstract_inverted_index.entrance	219
abstract_inverted_index.evidence	405
abstract_inverted_index.explains	243
abstract_inverted_index.findings	452
abstract_inverted_index.function	72, 155, 464
abstract_inverted_index.heparin.	293
abstract_inverted_index.inducing	17
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abstract_inverted_index.modulate	461
abstract_inverted_index.occupied	418
abstract_inverted_index.previous	315
abstract_inverted_index.protease	23, 48, 58, 275
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abstract_inverted_index.residues	298
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abstract_inverted_index.solution	147
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abstract_inverted_index.thrombin	63, 229
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abstract_inverted_index.bio-layer	133
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abstract_inverted_index.cofactors	10
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abstract_inverted_index.correlate	383
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abstract_inverted_index.function.	96
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abstract_inverted_index.proteases	2
abstract_inverted_index.structure	184, 258, 295
abstract_inverted_index.substrate	163, 390
abstract_inverted_index.supported	476
abstract_inverted_index.truncated	113
abstract_inverted_index.'intrinsic	30
abstract_inverted_index.Co-crystal	183
abstract_inverted_index.Comparison	333
abstract_inverted_index.N-terminal	114
abstract_inverted_index.Objective:	75
abstract_inverted_index.allosteric	407
abstract_inverted_index.apo-enzyme	177
abstract_inverted_index.apo-state,	199
abstract_inverted_index.catalysis.	438
abstract_inverted_index.co-crystal	257
abstract_inverted_index.comparison	252
abstract_inverted_index.conditions	136
abstract_inverted_index.explaining	353
abstract_inverted_index.hemostatic	14, 471
abstract_inverted_index.homologous	60, 254
abstract_inverted_index.implicated	285
abstract_inverted_index.importance	455
abstract_inverted_index.inhibition	387
abstract_inverted_index.inhibitory	355
abstract_inverted_index.negligible	138
abstract_inverted_index.phenotype,	450
abstract_inverted_index.previously	284
abstract_inverted_index.proteases.	255
abstract_inverted_index.regulation	431
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abstract_inverted_index.thrombotic	449
abstract_inverted_index.(RR029205).	529
abstract_inverted_index.Background:	0
abstract_inverted_index.Coagulation	19
abstract_inverted_index.IXa-aptamer	144, 260
abstract_inverted_index.P01HL139420	479
abstract_inverted_index.anisotropy.	152
abstract_inverted_index.coagulation	5, 61
abstract_inverted_index.comparison,	225
abstract_inverted_index.diffraction	488
abstract_inverted_index.fluorogenic	162
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abstract_inverted_index.interfering	216
abstract_inverted_index.mutagenesis	316
abstract_inverted_index.recognition	429
abstract_inverted_index.recombinant	107
abstract_inverted_index.specificity	327
abstract_inverted_index.thrombosis.	18
abstract_inverted_index.transitions	87
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abstract_inverted_index.architecture	53
abstract_inverted_index.biotinylated	127
abstract_inverted_index.conformation	237
abstract_inverted_index.demonstrates	349
abstract_inverted_index.determinants	321
abstract_inverted_index.displacement	369
abstract_inverted_index.fluorescence	151
abstract_inverted_index.measurements	160
abstract_inverted_index.specifically	7
abstract_inverted_index.trypsin-like	57
abstract_inverted_index.anticoagulant	190, 291
abstract_inverted_index.antithrombin.	172, 397
abstract_inverted_index.aptamer-bound	342
abstract_inverted_index.conformation,	211
abstract_inverted_index.conformations	338
abstract_inverted_index.site-mediated	394
abstract_inverted_index.sub-nanomolar	323
abstract_inverted_index.allosterically	364, 460
abstract_inverted_index.conformational	79
abstract_inverted_index.interferometry	134
abstract_inverted_index.mass-transport	139
abstract_inverted_index.rearrangements	382
abstract_inverted_index.crystallography	99
abstract_inverted_index.substrate-bound	344
abstract_inverted_index.aptamer-mediated	386
abstract_inverted_index.substrate-binding	222
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