ALPHA-KAP IS AN ANCHORING PROTEIN FOR A NOVEL CAM KINASE-II ISOFORM IN SKELETAL-MUSCLE

Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) is present in a membrane-bound form that phosphorylates synapsin I on neuronal s ynaptic vesicles and the ryanodine receptor at skeletal muscle sarcopl asmic reticulum (SR), but it is unclear how this soluble enzyme is tar geted to membranes. We demonstrate that alpha KAP, a non-kinase protei n encoded by a gene within the gene of alpha-CaM kinase II, can target the CaM kinase II holoenzyme to the SR membrane. Our results indicate that alpha KAP (i) is anchored to the membrane via its N-terminal hyd rophobic domain, (ii) can co-assemble with catalytically competent CaM kinase II isoforms and target them to the membrane regardless of thei r state of activation, and (iii) is colocalized and associated with ra t skeletal muscle CaM kinase II in vivo, alpha KAP is therefore the fi rst demonstrated anchoring protein for CaM kinase II, CaM kinase II as sembled with alpha KAP retains normal enzymatic activity and the abili ty to become Ca2+-independent following autophosphorylation. A new var iant of beta-CaM kinase II, termed beta(M)-CaM kinase II, is one of th e predominant CaM kinase II isoforms associated with alpha KAP in skel etal muscle SR.