Solution structure of ZASP PDZ domain; implications for sarcomere ultrastructure and enigma family redundancy.
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.
Au
Yunghan
Y
National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, United Kingdom.
Atkinson
R Andrew
RA
Guerrini
Remo
R
Kelly
Geoff
G
Joseph
Catherine
C
Martin
Steven R
SR
Muskett
Frederick W
FW
Pallavicini
Alberto
A
Faulkner
Georgine
G
Pastore
Annalisa
A
D000185:Actinin / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D064211:Connectin; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D060588:LIM Domain Proteins; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009124:Muscle Proteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012518:Sarcomeres / Q000737:chemistry* / Q000378:metabolism
C401401:ACTN2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D064211:Connectin; D018398:Homeodomain Proteins; C120696:LDB3 protein, human; D060588:LIM Domain Proteins; D009124:Muscle Proteins; C577285:TTN protein, human; D000185:Actinin; D011494:Protein Kinases