Group:MUZIC:Myozenin
From Proteopedia
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| - | == FATZ == | + | == FATZ/Myozenin/Calsarcin protein family == |
| - | The | + | The '''f'''ilamin-C α-'''a'''ctinin '''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.<ref> PMID: 10984498</ref> 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. <ref>PMID: 20170660</ref> 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.<ref>PMID: 11114196</ref><ref>PMID: 11842093</ref> 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 can be considered as an adaptor molecule that support and maintains the Z-disc architecture. But on the other hand, | + | 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<ref>PMID: 15543153</ref>. Therefore, the FATZ protein family could be seen as one example of Z-disc proteins where signalling and structural support converge. |
| - | == | + | ==Sequence Annotation== |
| - | [[Image:FATZ.png|550px|left|thumb|FATZ-1 regions]]There is not prediction of canonical domains in the tertiary structure of FATZ | + | [[Image:FATZ.png|550px|left|thumb|FATZ-1 regions]]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),<ref>PMID: 11171996</ref>; 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).<ref>PMID: 11171996</ref><ref>PMID: 11842093</ref><ref>PMID: 19047374</ref><ref>PMID: 16076904</ref><ref>PMID: 11114196</ref><ref>PMID: 10984498</ref>. | |
| + | 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.<ref> PMID: 15810059 </ref> | ||
| + | [[Image:FATZbinding3.jpg|550px|left|thumb|Mapping of binding regions on FATZ]]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<ref>PMID: 11171996</ref>. | ||
| + | Moreover, FATZ-2 has been described as a negative modulator of the phosphatase activity of calcineurin. <ref>PMID: 15543153</ref> <!—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. <ref>PMID: 15543153</ref> Moreover, the study of families this disease has suggested that mutations X and Y in FAT-2 where associated with the pathology. <ref>PMID: 17347475 </ref>Nevertheless, another study has also shown that there was no correlation between the suggested mutations and the disease. <ref>PMID: 18591919</ref>. 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. | |
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| - | 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 | + | |
==References== | ==References== | ||
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Revision as of 10:34, 5 July 2011
Contents |
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
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]
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.
