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11دورية أكاديمية
المؤلفون: Przeradzka, Małgorzata A, Freato, Nadia, Boon-Spijker, Mariëtte, van Galen, Josse, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, Meijer, Alexander B
المساهمون: Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics
مصطلحات موضوعية: actor VIII, factor IXa, kinetics, surface plasmon resonance, Von Willebrand factor, Taverne
الوصف: BACKGROUND: The identity of the amino acid regions of factor VIII (FVIII) that contribute to factor IXa (FIXa) and Von Willebrand Factor (VWF) binding has not been fully resolved. Previously, we observed that replacing the FVIII C1 domain for the one of factor V (FV) markedly reduces VWF binding and cofactor function. Compared to the FV C1 domain, this implies that the FVIII C1 domain comprises unique surface-exposed elements involved in VWF and FIXa interaction. OBJECTIVE: The aim of this study is to identify residues in the FVIII C1 domain that contribute to VWF and FIXa binding. METHODS: Structures and primary sequences of FVIII and FV were compared to identify surface-exposed residues unique to the FVIII C1 domain. The identified residues were replaced into alanine residues to identify their role in FIXa and VWF interaction. This role was assessed employing surface plasmon resonance analysis studies and enzyme kinetic assays. RESULTS: Five surface-exposed hydrophobic residues unique to the FVIII C1 domain, i.e.: F2035, F2068, F2127, V2130, I2139 were identified. Functional analysis indicated that residues F2068, V2130 and especially F2127 contribute to VWF and/or FIXa interaction. Substitution into alanine of the also surface-exposed V2125, which is spatially next to F2127, affected only VWF binding. CONCLUSION: The surface-exposed hydrophobic residues in C1 domain contribute to cofactor function and VWF binding. These findings provide novel information on the fundamental role of the C1 domain in FVIII life-cycle.
وصف الملف: application/pdf
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12دورية أكاديمية
المؤلفون: Przeradzka, Małgorzata A., Freato, Nadia, Boon‐Spijker, Mariëtte, van Galen, Josse, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, Meijer, Alexander B.
المصدر: Journal of Thrombosis and Haemostasis ; volume 18, issue 2, page 364-372 ; ISSN 1538-7836
مصطلحات موضوعية: Hematology
الإتاحة: https://doi.org/10.1111/jth.14668Test
https://api.elsevier.com/content/article/PII:S1538783622015057?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1538783622015057?httpAccept=text/plainTest -
13دورية أكاديمية
المؤلفون: van Oorschot, Rinske, Hansen, Marten, Koornneef, Johanna M, Marneth, Anna E, Bergevoet, Saskia M, van Bergen, Maaike G J M, van Alphen, Floris P J, van der Zwaan, Carmen, Martens, Joost H A, Vermeulen, Michiel, Jansen, Pascal W T C, Baltissen, Marijke P A, Gorkom, Britta A P Laros-van, Janssen, Hans, Jansen, Joop H, von Lindern, Marieke, Meijer, Alexander B, van den Akker, Emile, van der Reijden, Bert A
المساهمون: Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics
الوصف: Dominant-negative mutations in the transcription factor Growth Factor Independence-1B (GFI1B), such as GFI1BQ287*, cause a bleeding disorder characterized by a plethora of megakaryocyte and platelet abnormalities. The deregulated molecular mechanisms and pathways are unknown. Here we show that both normal and Q287* mutant GFI1B interacted most strongly with the lysine specific demethylase-1 - REST corepressor - histone deacetylase (LSD1-RCOR-HDAC) complex in megakaryoblasts. Sequestration of this complex by GFI1BQ287* and chemical separation of GFI1B from LSD1 induced abnormalities in normal megakaryocytes comparable to those seen in patients. Megakaryocytes derived from GFI1BQ287*-induced pluripotent stem cells also phenocopied abnormalities seen in patients. Proteome studies on normal and mutant-induced pluripotent stem cell-derived megakaryocytes identified a multitude of deregulated pathways downstream of GFI1BQ287* including cell division and interferon signaling. Proteome studies on platelets from GFI1BQ287* patients showed reduced expression of proteins implicated in platelet function, and elevated expression of proteins normally downregulated during megakaryocyte differentiation. Thus, GFI1B and LSD1 regulate a broad developmental program during megakaryopoiesis, and GFI1BQ287* deregulates this program through LSD1-RCOR-HDAC sequestering.
وصف الملف: image/pdf
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14دورية أكاديمية
المؤلفون: Przeradzka, Małgorzata A, Meems, Henriet, van der Zwaan, Carmen, Ebberink, Eduard H T M, van den Biggelaar, Maartje, Mertens, Koen, Meijer, Alexander B
المساهمون: Pharmaceutics, Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics
مصطلحات موضوعية: Taverne
الوصف: The D'-D3 fragment of von Willebrand factor (VWF) can be divided into TIL'-E'-VWD3-C8_3-TIL3-E3 subdomains of which TIL'-E'-VWD3 comprises the main factor VIII (FVIII)-binding region. Yet, von Willebrand disease (VWD) Type 2 Normandy (2N) mutations, associated with impaired FVIII interaction, have been identified in C8_3-TIL3-E3. We now assessed the role of the VWF (sub)domains for FVIII binding using isolated D', D3 and monomeric C-terminal subdomain truncation variants of D'-D3. Competitive binding assays and surface plasmon resonance analysis revealed that D' requires the presence of D3 for effective interaction with FVIII. The isolated D3 domain, however, did not show any FVIII binding. Results indicated that the E3 subdomain is dispensable for FVIII binding. Subsequent deletion of the other subdomains from D3 resulted in a progressive decrease in FVIII-binding affinity. Chemical footprinting mass spectrometry suggested increased conformational changes at the N-terminal side of D3 upon subsequent subdomain deletions at the C-terminal side of the D3. A D'-D3 variant with a VWD type 2N mutation in VWD3 (D879N) or C8_3 (C1060R) also revealed conformational changes in D3, which were proportional to a decrease in FVIII-binding affinity. A D'-D3 variant with a putative VWD type 2N mutation in the E3 subdomain (C1225G) showed, however, normal binding. This implies that the designation VWD type 2N is incorrect for this variant. Results together imply that a structurally intact D3 in D'-D3 is indispensable for effective interaction between D' and FVIII explaining why specific mutations in D3 can impair FVIII binding.
وصف الملف: application/pdf
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15دورية أكاديمية
المؤلفون: Stokhuijzen, Eva, Koornneef, Johanna M, Nota, Benjamin, van den Eshof, Bart Laurens, van Alphen, Floris Pieter Joachim, van den Biggelaar, Maartje, Van Der Zwaan, Carmen, Kuijk, Carlijn, Mertens, Koen, Fijnvandraat, Karin, Meijer, Alexander Benjamin
المساهمون: Afd Pharmaceutics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics
مصطلحات موضوعية: cord blood, mass spectrometry, platelets, proteome, Taverne
الوصف: It has been proposed that differences may exist between umbilical cord blood (CB) platelets and adult peripheral blood (APB) platelets, including altered protein levels of the main platelet integrins. We have now compared the protein expression profiles of CB and APB platelets employing a label-free comparative proteomics approach. Aggregation studies showed that CB platelets effectively aggregate in the presence of thromboxane A2 analogue, collagen, and peptide agonists of the proteinase-activated receptors 1 and 4. In agreement with previous studies, higher concentrations of the agonists were required to initiate aggregation in the CB platelets. Mass spectrometry analysis revealed no significant difference in the expression levels of critical platelet receptors like glycoprotein (GP)Ib, GPV, GPIX, and integrin αIIbβ3. This was confirmed using flow cytometry-based approaches. Gene ontology enrichment analysis revealed that elevated proteins in CB platelets were in particular enriched in proteins contributing to mitochondrial energy metabolism processes. The reduced proteins were enriched in proteins involved in, among others, platelet degranulation and activation. In conclusion, this study reveals that the CB and APB platelets are distinct. In particular, changes were observed for proteins that belong to metabolic and energy generation processes and not for the critical adhesive platelet integrins and glycoproteins.
وصف الملف: application/pdf
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16دورية أكاديمية
المؤلفون: Simionato, Greta (author), Rabe, Antonia (author), Gallego Murillo, Joan Sebastián (author), van der Zwaan, Carmen (author), Hoogendijk, A. J. (author), van den Biggelaar, Maartje (author), Minetti, Giampaolo (author), Bogdanova, Anna (author), Mairbäurl, Heimo (author)
مصطلحات موضوعية: High altitude, Hypoxia, In vitro erythropoiesis, Neocytolysis, PO
الوصف: Hypoxia is associated with increased erythropoietin (EPO) release to drive erythropoiesis. At high altitude, EPO levels first increase and then decrease, although erythropoiesis remains elevated at a stable level. The roles of hypoxia and related EPO adjustments are not fully understood, which has contributed to the formulation of the theory of neocytolysis. We aimed to evaluate the role of oxygen exclusively on erythropoiesis, comparing in vitro erythroid differentiation performed at atmospheric oxygen, a lower oxygen concentration (three percent oxygen) and with cultures of erythroid precursors isolated from peripheral blood after a 19-day sojourn at high altitude (3450 m). Results highlight an accelerated erythroid maturation at low oxygen and more concave morphology of reticulocytes. No differences in deformability were observed in the formed reticulocytes in the tested conditions. Moreover, hematopoietic stem and progenitor cells isolated from blood affected by hypoxia at high altitude did not result in different erythroid development, suggesting no retention of a high-altitude signature but rather an immediate adaptation to oxygen concentration. This adaptation was observed during in vitro erythropoiesis at three percent oxygen by a significantly increased glycolytic metabolic profile. These hypoxia-induced effects on in vitro erythropoiesis fail to provide an intrinsic explanation of the concept of neocytolysis. ; BT/Bioprocess Engineering
العلاقة: http://www.scopus.com/inward/record.url?scp=85126950658&partnerID=8YFLogxKTest; Cells--2073-4409--8b4eadf1-f52c-4ac0-b02b-535f86ec04a8; http://resolver.tudelft.nl/uuid:ac1a6a40-ffc0-437e-bab5-a21cae73299cTest; https://doi.org/10.3390/cells11071082Test
الإتاحة: https://doi.org/10.3390/cells11071082Test
http://resolver.tudelft.nl/uuid:ac1a6a40-ffc0-437e-bab5-a21cae73299cTest -
17دورية أكاديمية
المؤلفون: Van Den Biggelaar, Maartje, Madsen, Jesper J., Faber, Johan H., Zuurveld, Marleen G., Van Der Zwaan, Carmen, Olsen, Ole H., Stennicke, Henning R., Mertens, Koen, Meijer, Alexander B.
المساهمون: Sub Pharmaceutical proteins, UIPS - Utrecht Institute for Pharmaceutical Sciences
مصطلحات موضوعية: Taverne, Biochemistry, Cell Biology, Molecular Biology
الوصف: Background: It is unclear how the LDL receptor family binds large protein ligands. Results: HDX and lysine scanning identified factor (F)VIII regions and specific lysine residues binding low-density lipoprotein receptor-related protein 1 (LRP1). Conclusion: FVIII-LRP1 interaction involves multiple "hot-spot" lysine residues in the A3C1 domains. Significance: Our study sheds light on interactions of complex ligands with the LDL receptor family.
وصف الملف: application/pdf
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18دورية أكاديمية
المؤلفون: Bloem, Esther, Ebberink, Eduard H T M, van den Biggelaar, Maartje, van der Zwaan, Carmen, Mertens, Koen, Meijer, Alexander B
المساهمون: Sub Pharmaceutical proteins, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics
مصطلحات موضوعية: Amino Acid Sequence, Amino Acid Substitution, Animals, Binding Sites, Humans, LDL-Receptor Related Protein-Associated Protein, Low Density Lipoprotein Receptor-Related Protein-1, Lysine, Models, Molecular, Mutagenesis, Site-Directed, Protein Binding, Protein Footprinting, Protein Interaction Domains and Motifs, Rats, Recombinant Proteins, Tandem Mass Spectrometry, Taverne
الوصف: Tandem mass tags (TMTs) were utilized in a novel chemical footprinting approach to identify lysine residues that mediate the interaction of receptor-associated protein (RAP) with cluster II of LDL (low-density lipoprotein) receptor (LDLR)-related protein (LRP). The isolated RAP D3 domain was modified with TMT-126 and the D3 domain-cluster II complex with TMT-127. Nano-LC-MS analysis revealed reduced modification with TMT-127 of peptides including Lys(256), Lys(270) and Lys(305)-Lys(306) suggesting that these residues contribute to cluster II binding. This agrees with previous findings that Lys(256) and Lys(270) are critical for binding cluster II sub-domains [Fisher, Beglova and Blacklow (2006) Mol. Cell 22, 277-283]. Cluster II-binding studies utilizing D3 domain variants K(256)A, K(305)A and K(306)A now showed that Lys(306) contributes to cluster II binding as well. For full-length RAP, we observed that peptides including Lys(60), Lys(191), Lys(256), Lys(270) and Lys(305)-Lys(306) exhibited reduced modification with TMT in the RAP-cluster II complex. Notably, Lys(60) has previously been implicated to mediate D1 domain interaction with cluster II. Our results suggest that also Lys(191) of the D2 domain contributes to cluster II binding. Binding studies employing the RAP variants K(191)A, K(256)A, K(305)A and K(306)A, however, revealed a modest reduction in cluster II binding for the K(256)A variant only. This suggests that the other lysine residues can compensate for the absence of a single lysine residue for effective complex assembly. Collectively, novel insight has been obtained into the contribution of lysine residues of RAP to cluster II binding. In addition, we propose that TMTs can be utilized to identify lysine residues critical for protein complex formation.
وصف الملف: application/pdf
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19دورية أكاديمية
المؤلفون: van Galen, Josse, Freato, Nadia, Przeradzka, Małgorzata A., Ebberink, Eduard H.T.M., Boon-Spijker, Mariëtte, van der Zwaan, Carmen, van den Biggelaar, Maartje, Meijer, Alexander B.
المساهمون: Landsteiner Stichting voor Bloedtransfusie Research
المصدر: Thrombosis and Haemostasis ; volume 121, issue 05, page 594-602 ; ISSN 0340-6245 2567-689X
الوصف: Hydrogen–deuterium exchange mass spectrometry (HDX-MS) was employed to gain insight into the changes in factor VIII (FVIII) that occur upon its activation and assembly with activated factor IX (FIXa) on phospholipid membranes. HDX-MS analysis of thrombin-activated FVIII (FVIIIa) revealed a marked increase in deuterium incorporation of amino acid residues along the A1–A2 and A2–A3 interface. Rapid dissociation of the A2 domain from FVIIIa can explain this observation. In the presence of FIXa, enhanced deuterium incorporation at the interface of FVIIIa was similar to that of FVIII. This is compatible with the previous finding that FIXa contributes to A2 domain retention in FVIIIa. A2 domain region Leu631-Tyr637, which is not part of the interface between the A domains, also showed a marked increase in deuterium incorporation in FVIIIa compared with FVIII. Deuterium uptake of this region was decreased in the presence of FIXa beyond that observed in FVIII. This implies that FIXa alters the conformation or directly interacts with this region in FVIIIa. Replacement of Val634 in FVIII by alanine using site-directed mutagenesis almost completely impaired the ability of the activated cofactor to enhance the activity of FIXa. Surface plasmon resonance analysis revealed that the rates of A2 domain dissociation from FVIIIa and FVIIIa-Val634Ala were indistinguishable. HDX-MS analysis showed, however, that FIXa was unable to retain the A2 domain in FVIIIa-Val634Ala. The combined results of this study suggest that the local structure of Leu631-Tyr637 is altered by FIXa and that this region contributes to the cofactor function of FVIII.
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20دورية أكاديمية
المؤلفون: Castro-Núñez, Lydia, Bloem, Esther, Boon-Spijker, Mariëtte G., van der Zwaan, Carmen, van den Biggelaar, Maartje, Mertens, Koen, Meijer, Alexander B.
المصدر: Journal of Biological Chemistry ; volume 288, issue 1, page 393-400 ; ISSN 0021-9258
مصطلحات موضوعية: Cell Biology, Molecular Biology, Biochemistry
الإتاحة: https://doi.org/10.1074/jbc.m112.400572Test
https://api.elsevier.com/content/article/PII:S0021925820653455?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0021925820653455?httpAccept=text/plainTest
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