Group:MUZIC:Enigma Family: Difference between revisions

(13 intermediate revisions by one other user not shown)

Line 1:

==~~Enigma subfamily: PDZ/LIM-domain proteins of the cytoskeleton~~==

==Introduction==

Three member proteins have extensively been described and characterized within this subfamily: '''Enigma''' protein, '''Enigma Homologue''' (ENH) protein and '''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.

'''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 ~~and domain organization~~==

==Sequence annotation==

[[Image:Enigma_family.png|~~right~~|thumb|~~600px~~| PDZ- and LIM-domains map in the first isoforms of human Enigma subfamily members:

[[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>.

Line 17:

Line 16:

'''Enigma''' protein

alternatively referred to as PDLIM7 (PDZ and LIM domain protein 7) is the first and representative member of the Enigma subfamily. Initially characterized in human as ~49.85 kDa, 457 amino-acid protein with an N-terminal PDZ domain and three C-terminal LIM domains <ref>PMID:7929196</ref> <ref>PMID:10359609</ref>. Five alternatively spliced isoforms are presently identified (UniProtKB ID: Q9NR12)[http://www.uniprot.org/uniprot/Q9NR12#section_features].

==Structure==

<Structure load='1RGW' size='200' frame='true' align='right' caption='NMR solution structure of PDZ domain of ZASP (PDB ID: 1RGW) [http://www.rcsb.org/pdb/explore/explore.do?structureId=1RGW]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/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 models are depicted below from left to right. All member protein PDZ structures revealed canonical PDZ domain fold containing six β-strands and 2 α-helices [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY], except the '''PDZ domain of ZASP''' which has an extra α-helix between the third and fourth β-strand.

'''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==

Line 59:

Line 39:

==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>.

The presence of multiple mutations in the ZASP gene in patients

Line 67:

Line 47:

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).

==References==

@@ Line 1: / Line 1: @@
-==Enigma subfamily: PDZ/LIM-domain proteins of the cytoskeleton==
+==Introduction==
-Three member proteins have extensively been described and characterized within this subfamily: '''Enigma''' protein, '''Enigma Homologue''' (ENH) protein and '''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.
+'''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 and domain organization==
+==Sequence annotation==
-[[Image:Enigma_family.png|right|thumb|600px| PDZ- and LIM-domains map in the first isoforms of human Enigma subfamily members:
+[[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>.
@@ Line 17: / Line 16: @@
 '''Enigma''' protein
 alternatively referred to as PDLIM7 (PDZ and LIM domain protein 7) is the first and representative member of the Enigma subfamily. Initially characterized in human as ~49.85 kDa, 457 amino-acid protein with an N-terminal PDZ domain and three C-terminal LIM domains <ref>PMID:7929196</ref> <ref>PMID:10359609</ref>. Five alternatively spliced isoforms are presently identified (UniProtKB ID: Q9NR12)[http://www.uniprot.org/uniprot/Q9NR12#section_features].
 ==Structure==
-<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'/>
+<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='ENH_PDZ.pdb' size='200' frame='true' align='right' caption='NMR solution structure of PDZ domain of Enigma Homologue protein (PDB ID: 1WF7) [http://www.rcsb.org/pdb/explore/explore.do?structureId=1WF7]' scene='User:Adekunle_Onipe/workbench/Enigma_Family/Enh_pdz/5' />
-<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='1RGW' size='200' frame='true' align='right' caption='NMR solution structure of PDZ domain of ZASP (PDB ID: 1RGW) [http://www.rcsb.org/pdb/explore/explore.do?structureId=1RGW]' scene='User:Adekunle_Onipe/workbench/ZASP/Zasp_pdz_domain/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 models are depicted below from left to right.  All member protein PDZ structures revealed canonical PDZ domain fold containing six β-strands and 2 α-helices [http://smart.embl-heidelberg.de/smart/do_annotation.pl?DOMAIN=PDZ&BLAST=DUMMY], except the '''PDZ domain of ZASP''' which has an extra α-helix between the third and fourth β-strand.
+<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==
@@ Line 59: / Line 39: @@
 ==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>.
 The presence of multiple mutations in the ZASP gene in patients
@@ Line 67: / Line 47: @@
 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).
 ==References==
 <references/>