TAILIEUCHUNG - Báo cáo khoa học: Actin mutations in hypertrophic and dilated cardiomyopathy cause inefficient protein folding and perturbed filament formation

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most common hereditary cardiac conditions. Both are frequent causes of sudden death and are often associated with an adverse disease actinis one of the disease genes where different mis-sense mutations have been found to cause either HCM or DCM. We have tested the hypothesis that the protein-folding pathway plays a role in dis-ease development for two actin variants associated with DCM and six asso-ciated with HCM | ềFEBS Journal Actin mutations in hypertrophic and dilated cardiomyopathy cause inefficient protein folding and perturbed filament formation S0ren Vang1 Thomas J. Corydon2 Anders D. B0rglum2 Melissa D. Scott3 Judith Frydman3 Jens Mogensen4 Niels Gregersen1 and Peter Bross1 1 Research Unit for Molecular Medicine Aarhus University Hospitaland Faculty of Health Sciences Denmark 2 Institute of Human Genetics University of Aarhus Denmark 3 Department of BiologicalSciences and BioX Program Stanford University CA USA 4 Department of Cardiology Aarhus University Hospital Denmark Keywords a-cardiac actin chaperone dilated cardiomyopathy hypertrophic cardiomyopathy protein folding Correspondence S. Vang Research Unit for Molecular Medicine Aarhus University Hospital Skejby Sygehus Brendstrupgaardsvej DK-8200 Arhus N Denmark Fax 45 89496018 Tel 45 89495150 E-mail vang@ Received 12 January 2005 revised 24 February 2005 accepted 25 February 2005 doi Hypertrophic cardiomyopathy HCM and dilated cardiomyopathy DCM are the most common hereditary cardiac conditions. Both are frequent causes of sudden death and are often associated with an adverse disease course. Alpha-cardiac actin is one of the disease genes where different missense mutations have been found to cause either HCM or DCM. We have tested the hypothesis that the protein-folding pathway plays a role in disease development for two actin variants associated with DCM and six associated with HCM. Based on a cell-free coupled translation assay the actin variants could be graded by their tendency to associate with the chaperonin TCP-1 ring complex chaperonin containing TCP-1 TRiC CCT as well as their propensity to acquire their native conformation. Some variant proteins are completely stalled in a complex with TRiC and fail to fold into mature globular actin and some appear to fold as efficiently as the wildtype protein. A fraction of the translated polypeptide became ubiquitinated and .

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