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Molecular and Cellular Biology, February 2009, p. 822-834, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.01454-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Class III PDZ Binding Motif in the Myotilin and FATZ Families Binds Enigma Family Proteins: a Common Link for Z-Disc Myopathies{triangledown}

Pernilla von Nandelstadh,1,{dagger} Mohamed Ismail,2,{dagger},{ddagger} Chiara Gardin,3 Heli Suila,1 Ivano Zara,3 Anna Belgrano,2 Giorgio Valle,3 Olli Carpen,1,4,§ and Georgine Faulkner2,§*

Department of Pathology and Neuroscience Program, Biomedicum Helsinki, P.O. Box 63, Haartmninkatu 8, 00014 University of Helsinki, Helsinki, Finland,1 Muscle Molecular Biology, International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy,2 Department of Biology and CRIBI Biotechnology Centre, University of Padova, Via Ugo Bassi 58b, 35131 Padua, Italy,3 Department of Pathology, University of Turku and Turku University Central Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland4

Received 16 September 2008/ Returned for modification 24 October 2008/ Accepted 20 November 2008

Interactions between Z-disc proteins regulate muscle functions and disruption of these interactions results in muscle disorders. Mutations in Z-disc components myotilin, ZASP/Cypher, and FATZ-2 (calsarcin-1/myozenin-2) are associated with myopathies. We report here that the myotilin and the FATZ (calsarcin/myozenin) families share high homology at their final C-terminal five amino acids. This C-terminal E[ST][DE][DE]L motif is present almost exclusively in these families and is evolutionary conserved. We show by in vitro and in vivo studies that proteins from the myotilin and FATZ (calsarcin/myozenin) families interact via this novel type of class III PDZ binding motif with the PDZ domains of ZASP/Cypher and other Enigma family members: ALP, CLP-36, and RIL. We show that the interactions can be modulated by phosphorylation. Calmodulin-dependent kinase II phosphorylates the C terminus of FATZ-3 (calsarcin-3/myozenin-3) and myotilin, whereas PKA phosphorylates that of FATZ-1 (calsarcin-2/myozenin-1) and FATZ-2 (calsarcin-1/myozenin-1). This is the first report of a binding motif common to both the myotilin and the FATZ (calsarcin/myozenin) families that is specific for interactions with Enigma family members.

* Corresponding author. Mailing address: Muscle Molecular Biology, ICGEB, Padriciano 99, 34012 Trieste, Italy. Phone: 39-040-3757323. Fax: 39-040-226555. E-mail: faulkner{at}icgeb.org

{triangledown} Published ahead of print on 1 December 2008.

{dagger} P. von Nandelstadh and M. Ismail contributed equally to this paper.

{ddagger} Present address: Conway Institute, University College Dublin, Dublin 4, Ireland.

§ O. Carpen and G. Faulkner contributed equally to this paper.

Molecular and Cellular Biology, February 2009, p. 822-834, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.01454-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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