Tissue-specific expression and alpha-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs.
Titins are giant filamentous proteins which connect Z-discs and M-lines in the sarcomeres of vertebrate striated muscles. Comparison of the N-terminal region of titin (Z-disc region) from different skeletal and cardiac muscles reveals a 900-residue segment which is expressed in different length variants, dependent on tissue type. When searching for ligands of this differentially expressed domain by a yeast-two hybrid approach, we detected binding to alpha-actinin. The isolated alpha-actinin cDNAs were derived from the C-terminal region of the alpha-actinin isoform (alpha-actinin-2) encoded by the ACTN2 gene. Therefore, the two antiparallel subunits of an alpha-actinin-2 homodimer will attach to actin at their respective C termini, whereas they will bind to the Z-disc titin at their N termini. This may thus explain how alpha-actinins can cross-link antiparallel titin and thin filaments from opposing sarcomeres. The alpha-actinin-2 binding site of the Z-disc titin is located within a sequence of 45-residue repeats, referred to as Z-repeat region. Both the N-terminal and C-terminal Z-repeats have alpha-actinin binding properties and are expressed in all striated muscles. By contrast, the more central Z-repeats are expressed in slow and fast skeletal muscles, as well as embryonic and adult cardiac muscles, in different copy numbers. Such alternative splicing of the Z-disc titin appears to be important for the tissue and fibre type diversity of the Z-disc lattice.
Sorimachi
H
H
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113, Japan.
Freiburg
A
A
Kolmerer
B
B
Ishiura
S
S
Stier
G
G
Gregorio
C C
CC
Labeit
D
D
Linke
W A
WA
Suzuki
K
K
Labeit
S
S
D000185:Actinin / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D064211:Connectin; D015870:Gene Expression; D006801:Humans; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D011817:Rabbits; D012091:Repetitive Sequences, Nucleic Acid; D017386:Sequence Homology, Amino Acid; D014714:Vertebrates
D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; D000185:Actinin; D011494:Protein Kinases