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Solution structure of ZASP PDZ domain; implications for sarcomere ultrastructure and enigma family redundancy

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Au, Yunghan | Atkinson, Andrew | Guerrini, Remo | Kelly, Geoff | Joseph, Catherine | Martin, Steven R. | Muskett, Frederick W. | Pallavicini, Alberto | Faulkner, Georgine | Pastore, Annalisa

Edité par CCSD ; Elsevier (Cell Press) -

Z band alternately spliced PDZ-containing protein (ZASP) is a sarcomere Z disk protein expressed in human cardiac and skeletal muscle that is thought to be involved in a dominant familial dilated cardiomyopathy. The N-terminal PDZ domain of ZASP interacts with the C terminus of alpha-actinin-2, the major component of the Z disk, probably by forming a ternary complex with titin Z repeats. We have determined the structure of ZASP PDZ by NMR and showed that it is a classical class 1 PDZ domain that recognizes the carboxy-terminal sequence of an alpha-actinin-2 calmodulin-like domain with micromolar affinity. We also characterized the role of each component in the ternary complex ZASP/alpha-actinin-2/titin, showing that the alpha-actinin-2/ZASP PDZ interaction involves a binding surface distinct from that recognized by the titin Z repeats. ZASP PDZ structure was used to model other members of the enigma family by homology and to predict their abilities to bind alpha-actinin-2.

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