PDZ and LIM domains are modular protein interaction motifs present in prote
ins with diverse functions. Enigma is representative of a family of protein
s composed of a series of conserved PDZ and LIM domains. The LIM domains of
Enigma and its most related family member, Enigma homology protein, bind t
o protein kinases, whereas the PDZ domains of Enigma and family member acti
n-associated LIM protein bind to actin filaments. Enigma localizes to actin
filaments in fibroblasts via its PDZ domain, and actin-associated LIM prot
ein binds to and colocalizes with the actin-binding protein alpha-actinin-2
at Z lines in skeletal muscle. We show that Enigma is present at the Z lin
e in skeletal muscle and that the PDZ domain of Enigma binds to a skeletal
muscle target, the actin-binding protein tropomyosin (skeletal beta-TM). Th
e interaction between Enigma and skeletal beta-TM was specific for the PDZ
domain of Enigma, was abolished by mutations in the PDZ domain, and require
d the PDZ-binding consensus sequence (Thr-Ser-Leu) at the extreme carboxyl
terminus of skeletal beta-TM. Enigma interacted with isoforms of tropomyosi
n expressed in C2C12 myotubes and formed an immunoprecipitable complex with
skeletal beta-TM in transfected cells. The association of Enigma with skel
etal beta-TM suggests a role for Enigma as an adapter protein that directs
LIM-binding proteins to actin filaments of muscle cells.