Group:MUZIC:Enigma Family: Difference between revisions
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== | ==Introduction== | ||
Three member proteins have extensively been described and characterized within this subfamily: '''Enigma''' protein, '''Enigma Homologue''' (ENH) protein and '''ZASP/Cypher/Oracle''' ( | '''Enigma subfamily: PDZ/LIM-domain proteins of the cytoskeleton'''. Three member proteins have extensively been described and characterized within this subfamily: '''Enigma''' protein, '''Enigma Homologue''' (ENH) protein and '''[http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP ZASP/Cypher/Oracle]''' (ZASP<ref>PMID:10427098</ref> being the human orthologue of cypher<ref>PMID:10391924</ref> in mouse, also identified by independent researchers as oracle<ref>PMID:10727866</ref>). The family name - ''Enigma'' - possibly was inspired by the intricately complicated splice variants identified in the first member, a common feature in all member proteins, as well as their redundant, indinstinct functions in the cytoskeleton. Didactically, protein members of the enigma subfamily typically possess within their structure: '''(1)''' an N-terminal PDZ domain (domain named after first three proteins where it was initially characterized i.e. '''P'''SD 95, '''D'''isc large protein and '''Z'''onula Occludens 1), and '''(2)''' three C-terminal LIM domains (domain named after three proteins where it was first characterized '''L'''in-11, '''I'''sl1 and '''M'''ec-3)<ref>PMID:20042479</ref>. The Enigma member proteins have all been located to the mammalian muscle cells, some specific to the heart and skeletal muscle Z-disk. They interact via their PDZ domains with protein components of the Z-disk and also recruit signalling molecules via their LIM domains or internal motifs, for example ''ZM motif'' (ZASP-like motif which is sandwiched between the PDZ- and LIM-domains in ZASP)<ref>doi:10.1161/CIRCRESAHA.110.225615</ref>. These interactions via their PDZ- and LIM-domains suggest roles important for targeting/sustaining interacting protein complexes within the myofibrillar sarcomere for a physiologically functional muscle. | ||
==Sequence annotation | ==Sequence annotation== | ||
[[Image:Enigma_family.png|left|thumb| | [[Image:Enigma_family.png|left|thumb|450px| PDZ- and LIM-domains map in the first isoforms of human Enigma subfamily members: | ||
'''ZASP''' [http://www.uniprot.org/uniprot/O75112#section_features)]'''ENH''' [http://www.uniprot.org/uniprot/Q96HC4#section_alternative]'''Enigma''' [http://www.uniprot.org/uniprot/Q9NR12#section_features]]] | |||
'''[http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP ZASP]''' ('''Z'''-disk '''A'''lternatively '''S'''pliced '''P'''DZ domain protein), also referred to as LIM domain-binding protein 3 (LDB-3), is the 78 kDa, 727-amino-acid human ortholog of cypher, independently identified in heart and skeletal | |||
'''ZASP''' ('''Z'''-disk '''A'''lternatively '''S'''pliced '''P'''DZ domain protein), also referred to as LIM domain-binding protein 3 (LDB-3), is the 78 kDa, 727-amino-acid human ortholog of cypher, independently identified in heart and skeletal | |||
muscle<ref>PMID:10427098</ref>. Five alternatively spliced isoforms of ZASP have been identified (UniProtKB: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)]. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. | muscle<ref>PMID:10427098</ref>. Five alternatively spliced isoforms of ZASP have been identified (UniProtKB: O75112)[http://www.uniprot.org/uniprot/O75112#section_features)]. Apart from the PDZ domain, ZASP possess an internal motif (ZASP-like motif) which confers the ability to interact with the spectrin repeats of α-actinin-2 <ref>doi:10.1016/j.yexcr.2005.12.036</ref>. | ||
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==Structure== | ==Structure== | ||
<Structure load='LIM1.pdb' size='200' frame='true' align='right' caption='NMR solution structure of LIM-1 domain of Enigma Homologue protein (PDB ID: [[2dar]]) [http://www.rcsb.org/pdb/explore/explore.do?structureId=2DAR]' scene='User:Adekunle_Onipe/workbench/Enigma_Family/Enh_lim1/2' /> | |||
<Structure load='LIM1.pdb' size=' | |||
<Structure load='PDLIM7.pdb' size='200' frame='true' align='right' caption='X-ray crystal structure of PDZ domain of Enigma protein at 1.11Å (PDB ID: [[2q3g]] [http://www.rcsb.org/pdb/explore/explore.do?structureId=2Q3G]' scene='User:Adekunle_Onipe/workbench/Enigma_Family/Pdz_enigma/3'/> | |||
'''Molecular structures''' of PDZ domain(s) of the three member proteins have recently been solved. Likewise, the LIM-1 domain of Enigma Homologue protein has yielded its structure in atomic details. Structural model of all member proteins reveal canonical PDZ domain fold containing six β-strands (A-F) and 2 α-helices (A and B) [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY] | |||
==Function and Interactions== | ==Function and Interactions== | ||
In general, the PDZ domain(s) of Enigma subfamily have been structurally revealed as a classical | In general, the PDZ domain(s) of Enigma subfamily have been structurally revealed as a classical | ||
class I PDZ domain - this is suggested by its interaction with | class I PDZ domain - this is suggested by its interaction with | ||
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domain or additional internal domains (ZM-motif), recruit signaling proteins to implement corresponding functions (see <ref>doi:10.1093/jmcb/mjp038</ref>, and references therein). In addition, experimental evidences indicate Enigma protein may function as a scaffold on which the coordinated assembly of sarcomeric proteins can occur; largely owing to the interactions via its PDZ- and LIM domains with actin-associated proteins of cardiac and skeletal muscle, as well as non-muscle tissues [[<ref>PMID:7929196</ref>]]. It has also been implicated in bone formation and fracture repair<ref>PMID:11874232</ref>. It may also be involved in BMP6 signaling pathway. Generally, it interacts with various PKC isoforms using the LIM domains<ref>PMID:8940095</ref>. The LIM-2 domain has been shown to interact with TBX4, as well as RET in a phosphorylation-independent manner<ref>PMID:9528800</ref>. Despite the co-localization of '''Enigma protein''' with proteins in the Z-line and I-band, a definite functional role in the sarcomere has not | domain or additional internal domains (ZM-motif), recruit signaling proteins to implement corresponding functions (see <ref>doi:10.1093/jmcb/mjp038</ref>, and references therein). In addition, experimental evidences indicate Enigma protein may function as a scaffold on which the coordinated assembly of sarcomeric proteins can occur; largely owing to the interactions via its PDZ- and LIM domains with actin-associated proteins of cardiac and skeletal muscle, as well as non-muscle tissues [[<ref>PMID:7929196</ref>]]. It has also been implicated in bone formation and fracture repair<ref>PMID:11874232</ref>. It may also be involved in BMP6 signaling pathway. Generally, it interacts with various PKC isoforms using the LIM domains<ref>PMID:8940095</ref>. The LIM-2 domain has been shown to interact with TBX4, as well as RET in a phosphorylation-independent manner<ref>PMID:9528800</ref>. Despite the co-localization of '''Enigma protein''' with proteins in the Z-line and I-band, a definite functional role in the sarcomere has not | ||
been shown yet<ref>doi:10.1093/jmcb/mjp038</ref>; '''''which resounds the literal meaning of the word Enigma'''.'' | been shown yet<ref>doi:10.1093/jmcb/mjp038</ref>; '''''which resounds the literal meaning of the word Enigma'''.'' | ||
==Pathology== | ==Pathology== | ||
Mutations in the '''ZASP''' gene have been associated with dilated cardiomyopathy (DCM) and DCM | Mutations in the '''[http://proteopedia.org/wiki/index.php/Group:MUZIC:ZASP ZASP]''' gene have been associated with dilated cardiomyopathy (DCM) and DCM | ||
associated with isolated left ventricular noncompaction of the myocardium (INLVM) in humans <ref>PMID:14662268</ref>. | associated with isolated left ventricular noncompaction of the myocardium (INLVM) in humans <ref>PMID:14662268</ref>. | ||
The presence of multiple mutations in the ZASP gene in patients | The presence of multiple mutations in the ZASP gene in patients | ||
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various regions of the brain, suggest a possible role in brain development<ref>PMID:12665800</ref>. In accordance, ENH | various regions of the brain, suggest a possible role in brain development<ref>PMID:12665800</ref>. In accordance, ENH | ||
expression levels were found to be significantly increased in all brain regions of patients with bipolar disorder, schizophrenia, and major depression(see <ref>DOI 10.1100/tsw.2007.232</ref>, and references therein). | expression levels were found to be significantly increased in all brain regions of patients with bipolar disorder, schizophrenia, and major depression(see <ref>DOI 10.1100/tsw.2007.232</ref>, and references therein). | ||
==References== | ==References== | ||
<references/> | <references/> | ||