Group:MUZIC:Myozenin

From Proteopedia

proteopedia linkproteopedia link

Contents 1 FATZ/Myozenin/Calsarcin protein family 2 Sequence Annotation 3 FATZ interactions and their physiological role 4 Association of hypertrophic cardiomyopathy with FATZ-2 5 References

FATZ/Myozenin/Calsarcin protein family

The filamin-C α-actinin telethonin Z-disc binding protein (FATZ) is a protein family of three isoforms: FATZ-1, FATZ-2, FATZ-3, which are expressed in muscle cells.^[1] This protein family (also known as Myozenin or Calsarcin) is mainly localized in the Z-disc, although recently it has been described that FATZ-2 was found in cardiac nuclei. ^[2] The expression of the three isoforms has been shown to be fibre type specific as for instance: the members FATZ-1 and FATZ-3 are highly expressed in skeletal muscle fast twitch fibres while FATZ-2 is predominantly expressed in cardiac muscle slow-twitch fibres.^[3][4] Nevertheless, the three isoforms seems to have redundant function since all the three are sharing the same binding partners. Due to its Z-disc localization and multiple binding partners, FATZ proteins can be considered as an adaptor molecule that support and maintains the Z-disc architecture. But on the other hand, FATZ-2 has been shown to be a member of a signalling pathway controlling the cell response to pressure overload^[5]. Therefore, the FATZ protein family could be seen as one example of Z-disc proteins where signalling and structural support converge.

Sequence Annotation

There is not prediction of canonical domains in the tertiary structure of FATZ proteins, but for all of them there is a glycine rich region in the middle of the sequence.

Based on the prediction of secondary elements, it has been identified three regions on the sequence of FATZ-1: N-terminal CD1 (1-75), glycine rich region (GRR, 75-171) and C-terminal CD2 (172-299),^[6]; although there is no tridimensional model for the structure of any of the isoforms. <!—don’t forget to add uniprot links-->

FATZ interactions and their physiological role

Different interacting partners of FATZ proteins have been characterized by cellular and biochemical approaches. Screenings of yeast two-hybrid assays allowed identifying interactions with other Z-disc proteins as α-actinin-2, filamin-C, myotilin, telethonin, calcineurin and ZASP/Cypher( in general Enigma family protein).^{[7][8][9][10][11][12]}. At the moment it is though that interaction with α-actinin-2, filamin-C, myotilin, telethonin and ZASP contributes to maintain the Z-disc scaffold. Although is worth mentioning that it has been suggested to play some role in myofibril formation, since FATZ-1 has been seen in premyofibrils as α-actinin-2, filamin-C, myotilin, while titin and telethonin has been seen in more advanced stages.^[13]

Most of the mapping of the binding regions where done by screening dna libraries with the yeast two-hybrid assays and furthermore confirmed by co-immunoprecipitation or pull down assays. Many interacting partners have their binding sites in the C-terminal of FATZs while others in the N-terminal region. In some cases as for a-actinin-2 and filamin-C, there is competitively binding, even though the physiological relevance of such competition is not yet understood^[14].

Moreover, FATZ-2 has been described as a negative modulator of the phosphatase activity of calcineurin. ^[15] <!—link to calcineurin page-->. Therefore by preventing dephosphorylation activity of calcineurin, this interaction involves FATZ protein family in a signalling pathway controlling the cell response to pressure overload.

Association of hypertrophic cardiomyopathy with FATZ-2

In experimental models, it has been shown that the absence of FATZ-2 led to up-regulation of calcineurin phosphatase activity and cellular proliferation, thereby inducing hypertrophic cardiomyopathy. ^[16] Moreover, the study of families this disease has suggested that mutations X and Y in FAT-2 where associated with the pathology. ^[17]Nevertheless, another study has also shown that there was no correlation between the suggested mutations and the disease. ^[18]. Given that, whether FATZ-2 is a marker of hypertrophic cardiomyopathy or not is still under discussion and more studies shall be done to clearly define its physiological role in cardiomyocyte.

References