Structural and functional differences between KRIT1A and KRIT1B isoforms: A framework for understanding CCM pathogenesis (704 views)
Exp Cell Res (ISSN: 0014-4827), 2009 Jan 15; 315(2): 285-303.
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Paper type: Journal Article,
Impact factor: 3.589, 5-year impact factor: 3.713
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-57749178396&partnerID=40&md5=d60bd5ddefa5969cb63596d69c0a090d
Keywords: Ccm, Ferm Domain, Head-To-Tail Protein Interaction, Homology Modeling, Icap1, Krit1, Ligand Docking, Nucleocytoplasmic Shuttling, Rap1a, Yeast Two-Hybrid Interaction, Cell Protein, Protein Krit1a, Rap1 Protein, Rap1a Protein, Unclassified Drug, Animal Cell, Article, Brain Malformation, Cellular Distribution, Cerebral Cavernous Malformation, Controlled Study, Exon, Molecular Model, Nonhuman, Nucleotide Sequence, Pathogenesis, Priority Journal, Protein Binding, Protein Domain, Protein Localization, Protein Protein Interaction, Protein Structure, Protein Transport, Sequence Homology, Structure Activity Relation, Cell Line, Central Nervous System Vascular Malformations, Cercopithecus Aethiops, Computer Simulation, Cos Cells, Hela Cells, Hemangioma, Intracellular Signaling Peptides And Proteins, Microfilament Proteins, Microtubule-Associated Proteins, Peptide Fragments, Point Mutation, Protein Interaction Domains And Motifs, Protein Isoforms, Secondary, Proto-Oncogene Proteins, Rap1 Gtp-Binding Proteins, Recombinant Fusion Proteins, Two-Hybrid System Techniques,
Affiliations:
*** IBB - CNR ***
Molecular Biotechnology Centre, Department of Genetics, Biology and Biochemistry, Via Nizza 52, 10126 Torino, Italy
Department of Molecular Biology, University of Siena, Italy
Department of Chemistry IFM, University of Torino, Italy
Institute of Biostructure and Bioimaging, National Research Council of Napoli, Italy
References:
Not available.
Exp Cell Res (ISSN: 0014-4827), 2009 Jan 15; 315(2): 285-303.
Export to BibTeX Export to EndNote
Paper type: Journal Article,
Impact factor: 3.589, 5-year impact factor: 3.713
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-57749178396&partnerID=40&md5=d60bd5ddefa5969cb63596d69c0a090d
Keywords: Ccm, Ferm Domain, Head-To-Tail Protein Interaction, Homology Modeling, Icap1, Krit1, Ligand Docking, Nucleocytoplasmic Shuttling, Rap1a, Yeast Two-Hybrid Interaction, Cell Protein, Protein Krit1a, Rap1 Protein, Rap1a Protein, Unclassified Drug, Animal Cell, Article, Brain Malformation, Cellular Distribution, Cerebral Cavernous Malformation, Controlled Study, Exon, Molecular Model, Nonhuman, Nucleotide Sequence, Pathogenesis, Priority Journal, Protein Binding, Protein Domain, Protein Localization, Protein Protein Interaction, Protein Structure, Protein Transport, Sequence Homology, Structure Activity Relation, Cell Line, Central Nervous System Vascular Malformations, Cercopithecus Aethiops, Computer Simulation, Cos Cells, Hela Cells, Hemangioma, Intracellular Signaling Peptides And Proteins, Microfilament Proteins, Microtubule-Associated Proteins, Peptide Fragments, Point Mutation, Protein Interaction Domains And Motifs, Protein Isoforms, Secondary, Proto-Oncogene Proteins, Rap1 Gtp-Binding Proteins, Recombinant Fusion Proteins, Two-Hybrid System Techniques,
Affiliations:
*** IBB - CNR ***
Molecular Biotechnology Centre, Department of Genetics, Biology and Biochemistry, Via Nizza 52, 10126 Torino, Italy
Department of Molecular Biology, University of Siena, Italy
Department of Chemistry IFM, University of Torino, Italy
Institute of Biostructure and Bioimaging, National Research Council of Napoli, Italy
References:
Not available.
Structural and functional differences between KRIT1A and KRIT1B isoforms: A framework for understanding CCM pathogenesis
KRIT1 is a disease gene responsible for Cerebral Cavernous Malformations (CCM). It encodes for a protein containing distinct protein-protein interaction domains, including three NPXY/F motifs and a FERM domain. Previously, we isolated KRIT1B, an isoform characterized by the alternative splicing of the 15th coding exon and suspected to cause CCM when abnormally expressed. Combining homology modeling and docking methods of protein-structure and ligand binding prediction with the yeast two-hybrid assay of in vivo protein-protein interaction and cellular biology analyses we identified both structural and functional differences between KRIT1A and KRIT1B isoforms. We found that the 15th exon encodes for the distal β-sheet of the F3/PTB-like subdomain of KRIT1A FERM domain, demonstrating that KRIT1B is devoid of a functional PTB binding pocket. As major functional consequence, KRIT1B is unable to bind Rap1A, while the FERM domain of KRIT1A is even sufficient for this function. Furthermore, we found that a functional PTB subdomain enables the nucleocytoplasmic shuttling of KRIT1A, while its alteration confers a restricted cytoplasmic localization and a dominant negative role to KRIT1B. Importantly, we also demonstrated that KRIT1A, but not KRIT1B, may adopt a closed conformation through an intramolecular interaction involving the third NPXY/F motif at the N-terminus and the PTB subdomain of the FERM domain, and proposed a mechanism whereby an open/closed conformation switch regulates KRIT1A nuclear translocation and interaction with Rap1A in a mutually exclusive manner. As most mutations found in CCM patients affect the KRIT1 FERM domain, the new insights into the structure-function relationship of this domain may constitute a useful framework for understanding molecular mechanisms underlying CCM pathogenesis. © 2008 Elsevier Inc. All rights reserved.
KRIT1 is a disease gene responsible for Cerebral Cavernous Malformations (CCM). It encodes for a protein containing distinct protein-protein interaction domains, including three NPXY/F motifs and a FERM domain. Previously, we isolated KRIT1B, an isoform characterized by the alternative splicing of the 15th coding exon and suspected to cause CCM when abnormally expressed. Combining homology modeling and docking methods of protein-structure and ligand binding prediction with the yeast two-hybrid assay of in vivo protein-protein interaction and cellular biology analyses we identified both structural and functional differences between KRIT1A and KRIT1B isoforms. We found that the 15th exon encodes for the distal β-sheet of the F3/PTB-like subdomain of KRIT1A FERM domain, demonstrating that KRIT1B is devoid of a functional PTB binding pocket. As major functional consequence, KRIT1B is unable to bind Rap1A, while the FERM domain of KRIT1A is even sufficient for this function. Furthermore, we found that a functional PTB subdomain enables the nucleocytoplasmic shuttling of KRIT1A, while its alteration confers a restricted cytoplasmic localization and a dominant negative role to KRIT1B. Importantly, we also demonstrated that KRIT1A, but not KRIT1B, may adopt a closed conformation through an intramolecular interaction involving the third NPXY/F motif at the N-terminus and the PTB subdomain of the FERM domain, and proposed a mechanism whereby an open/closed conformation switch regulates KRIT1A nuclear translocation and interaction with Rap1A in a mutually exclusive manner. As most mutations found in CCM patients affect the KRIT1 FERM domain, the new insights into the structure-function relationship of this domain may constitute a useful framework for understanding molecular mechanisms underlying CCM pathogenesis. © 2008 Elsevier Inc. All rights reserved.
Structural and functional differences between KRIT1A and KRIT1B isoforms: A framework for understanding CCM pathogenesis
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Structural and functional differences between KRIT1A and KRIT1B isoforms: A framework for understanding CCM pathogenesis
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* The zinc coordination pattern in the eta-carbonic anhydrase from Plasmodium falciparum is different from all other carbonic anhydrase genetic families (590 views)
Bioorg Med Chem Lett (ISSN: 0960-894x), 2015 Apr 1; 25(7): 1385-1389.
Impact Factor: 2.486
View Export to BibTeX Export to EndNote
Calvanese L, Marasco D, Doti N, Saporito A, D'Auria G, Paolillo L, Ruvo M, Falcigno L
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Biopolymers (ISSN: 0006-3525, 0006-6352, 0006-3525print), 2010 Nov; 93(11): 1011-1021.
Impact Factor: 2.572
View Export to BibTeX Export to EndNote
Alfieri A, Pasanisi F, Salzano S, Esposito L, Martone D, Tafuri D, Daniele A, Contaldo F, Sacchetti L, Zagari A, Buono P
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Gene (ISSN: 0378-1119), 2010 Jun 1; 457(1-2): 35-41.
Impact Factor: 2.266
View Export to BibTeX Export to EndNote
Palmieri G, Catara G, Saviano M, Langella E, Gogliettino M, Rossi M
* First archaeal PEPB-serine protease inhibitor from sulfolobus solfataricus with noncanonical amino acid sequence in the reactive-site loop (530 views)
J Proteome Res (ISSN: 1535-3893), 2009 Jan; 8(1): 327-334.
Impact Factor: 5.132
View Export to BibTeX Export to EndNote
Ragno R, Simeoni S, Castellano S, Vicidomini C, Mai A, Caroli A, Tramontano A, Bonaccini C, Trojer P, Bauer I, Brosch G, Sbardella G
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J Med Chem (ISSN: 0022-2623, 1520-4804, 0022-2623print), 2007 Mar 22; 50(6): 1241-1253.
Impact Factor: 4.895
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5 Records (5 excluding Abstracts).
Total impact factor: 17.351 (17.351 excluding Abstracts).
Total 5 year impact factor: 17.889 (17.889 excluding Abstracts).
Total impact factor: 17.351 (17.351 excluding Abstracts).
Total 5 year impact factor: 17.889 (17.889 excluding Abstracts).
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