Contribution of the different modules in the utrophin carboxy‐terminal region to the formation and regulation of the DAP complex

FEBS Letters

Di Zenzo, Giovanni²  Sudol, Marius¹  Dente, Luciana²  Tommasi di Vignano, Alice²  Cesareni, Gianni² 

[1] Department of Biochemistry, Mount Sinai-NYU Medical Center, One Gustave Levy Place, New York, NY 10029, USA;Department of Biology ‘Enrico Calef’, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy

关键词: Utrophin;    Calmodulin;    Phage display;    Modular domain;    Dystrophin-associated protein;    DRP2;   

DOI  :  10.1016/S0014-5793(00)01400-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The carboxy-terminal region of utrophin, like the homologous proteins dystrophin, Drp2 and dystrobrevins, contains structural domains frequently involved in protein–protein interaction. These domains (WW, EF hands, ZZ and H1–H2) mediate recognition and binding to a multicomponent complex of proteins, also known as dystrophin-associated proteins (DAPs) for their association with dystrophin, the product of the gene, mutated in Duchenne muscular dystrophy. We have exploited phage display and in vitro binding assays to study the recognition specificity of the different domains of the utrophin carboxy-terminus. We found that none of the carboxy-terminal domains of utrophin, when isolated from its structural context, selects specific ligand peptides from a phage-displayed peptide library. By contrast, panning with an extended region containing the WW, EF hands, and ZZ domain defines the consensus binding motif, PPxY which is also found in β-dystroglycan, a component of the DAP complex that interacts with utrophin in several tissues. WW-mediated binding to PPxY peptides and to β-dystroglycan requires the presence of the EF hands and ZZ domain. When the ZZ domain is either deleted or engaged in binding to calmodulin, the utrophin β-dystroglycan complex cannot be formed. These findings suggest a potential regulatory mechanism by means of which the attachment of utrophin to the DAP complex can be modulated by the Ca²⁺-dependent binding of calmodulin. The remaining two motifs found in the carboxy-terminus (H1–H2) mediate the formation of utrophin–dystrobrevin hybrids but do not select ligands in a repertoire of random nonapeptides.

【 授权许可】

Unknown