Research Report 2010 - MDC

Burcu SimsekRalf MeißnerTechnical AssistantsPetra SakelSteffen LutterKarin KarczewskiPetra DomaingSaskia ReichertSecretariatManuela KaadaFigure 1. 3D-model of the actomyosin complex. (A)Gauss–Connolly surfaces are used to visualize the molecularcomplex. Actin units are coloured orange, brown, and yellow.The myosin S1 head (green), the regulatory light chain (red), theshortened essential light chain (white), the 46 N-terminalresidues of A1 (blue), and clusters of acidic residues on actin(pink) are shown. (B) More detailed view on the potential interactionof N-terminal APKK of A1 with acidic residues on actin.Ionic interactions between lysine residues (K3 and K4) of APKKand acidic residues (E361 and E364) on actin were assumed.Figure 2. Proposed model for sympatheticcontrol of I CaL by ahnak1.Under basal conditions, I CaL carriedby the α1C-subunit is repressed bystrong ahnak1/β2-subunit binding(left panel). Upon sympathetic stimulation,PKA sites in ahnak1 and/or inβ2 become phosphorylated. Thisreleases the β2-subunit from ahnak1inhibition resulting in increased I CaL .The role of myomesin missense mutations on thegenesis of hypertrophic cardiomyopathyRomy Siegert (In collaboration with Cemil Öczelik,University Medicine Charité, Berlin and IrinaAgarkova, Universitäts-Spital, Zürich,)Hypertrophic cardiomyopathy (HCM) is a commoncause of sudden cardiac death in young people. Threemissense mutations in the myomesin gene haverecently been detected in patients with HCM. Thesemutations are located close to the myosin and titinbinding sites and the dimerization region. The aim ofthe project is to study the molecular pathomechanismscausing the development of HCM by myomesin mutations(e.g. V1490I). Therefore, functional properties ofmutated recombinant fusion proteins will analyzed, i.e.force measurements of poly-myomesin by atomic forcemicroscopy, structural properties by circular dichroismand melting curves, and cellular functions by transientexpression of normal and mutated myomesin domainsin cardiomyoblasts. Transgenetic rat lines which overexpressfunctionally relevant myomesin mutations willbe generated in order to investigate their potential tocause HCM.Cardiovascular and Metabolic Disease Research 13