http://www.cnr.it/ontology/cnr/individuo/prodotto/ID14077
Structural and functional differences between KRIT1A and KRIT1B isoforms: A framework for understanding CCM pathogenesis (Articolo in rivista)
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- Label
- Structural and functional differences between KRIT1A and KRIT1B isoforms: A framework for understanding CCM pathogenesis (Articolo in rivista) (literal)
- Anno
- 2009-01-01T00:00:00+01:00 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
- 10.1016/j.yexcr.2008.10.006 (literal)
- Alternative label
Francalanci, Floriana; Avolio, Maria; De Luca, Elisa; Longo, Dario; Menchise, Valeria; Guazzi, Paolo; Sgro, Francesco; Marino, Marco; Goitre, Luca; Balzac, Fiorella; Trabalzini, Lorenza; Retta, Saverio Francesco (2009)
Structural and functional differences between KRIT1A and KRIT1B isoforms: A framework for understanding CCM pathogenesis
in Experimental cell research
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- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
- Francalanci, Floriana; Avolio, Maria; De Luca, Elisa; Longo, Dario; Menchise, Valeria; Guazzi, Paolo; Sgro, Francesco; Marino, Marco; Goitre, Luca; Balzac, Fiorella; Trabalzini, Lorenza; Retta, Saverio Francesco (literal)
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- ISI Web of Science (WOS) (literal)
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- 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 (literal)
- Titolo
- Structural and functional differences between KRIT1A and KRIT1B isoforms: A framework for understanding CCM pathogenesis (literal)
- Abstract
- 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 ?-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. (literal)
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